Methods for treating cardiovascular disorders

ABSTRACT

The invention provides methods for identifying compounds suitable for treating a cardiovascular disorder, as well as methods for treating a cardiovascular disorder. The invention also provides methods for determining if a subject is at risk for a cardiovascular disorder.

RELATED APPLICATIONS

[0001] This application claims priority to U.S. provisional ApplicationNo. 60/110,033, filed on Nov. 25, 1998, U.S. provisional Application No.60/109,333, filed on Nov. 20, 1998, U.S. provisional Application No.60/110,277, filed on Nov. 30, 1998, and U.S. patent application Ser. No.09/298,731, filed on Apr. 23, 1999, incorporated herein in theirentirety by this reference.

BACKGROUND OF THE INVENTION

[0002] Mammalian cell membranes are important to the structuralintegrity and activity of many cells and tissues. Of particular interestin membrane physiology is the study of transmembrane ion channels whichact to directly control a variety of pharmacological, physiological, andcellular processes. Numerous ion channels have been identified includingcalcium, sodium, and potassium channels, each of which have beeninvestigated to determine their roles in vertebrate and insect cells.

[0003] Because of their involvement in maintaining normal cellularhomeostasis, much attention has been given to potassium channels. Anumber of these potassium channels open in response to changes in thecell membrane potential. Many voltage-gated potassium channels have beenidentified and characterized by their electrophysiological andpharmacological properties. Potassium currents are more diverse thansodium or calcium currents and are further involved in determining theresponse of a cell to external stimuli.

[0004] The diversity of potassium channels and their importantphysiological role highlights their potential as targets for developingtherapeutic agents for various diseases. One of the best characterizedclasses of potassium channels are the voltage-gated potassium channels.The prototypical member of this class is the protein encoded by theShaker gene in Drosophila melanogaster. Proteins of the Shal or Kv4family are a type of voltage-gated potassium channels that underliesmany of the native A type currents that have been recorded fromdifferent primary cells. Kv4 channels have a major role in therepolarization of cardiac action potentials. In neurons, Kv4 channelsand the A currents they may comprise play an important role inmodulation of firing rate, action potential initiation and incontrolling dendritic responses to synaptic inputs.

[0005] The Kv family of channels includes, among others: (1) thedelayed-rectifier potassium channels, which repolarize the membraneafter each action potential to prepare the cell to fire again; and (2)the rapidly inactivating (A-type) potassium channels, which are activepredominantly at subthreshold voltages and and act to reduce the rate atwhich excitable cells reach firing threshold. In addition to beingcritical for action potential conduction, Kv channels also control theresponse to depolarizing, e.g., synaptic, inputs and play a role inneurotransmitter release. As a result of these activities, voltage-gatedpotassium channels are key regulators of neuronal excitability (HilleB., Ionic Channels of Excitable Membranes, Second Edition, Sunderland,Mass.: Sinauer, (1992)).

[0006] There is tremendous structural and functional diversity withinthe Kv potassium channel superfamily. This diversity is generated bothby the existence of multiple genes and by alternative splicing of RNAtranscripts produced from the same gene. Nonetheless, the amino acidsequences of the known Kv potassium channels show high similarity. Allappear to be comprised of four, pore forming α-subunits and some areknown to have four cytoplasmic (β-subunit) polypeptides (Jan L. Y. etal. (1990) Trends Neurosci 13:415-419, and Pongs, O. et al. (1995) SemNeurosci. 7:137-146). The known Kv channel α-subunits fall into foursub-families named for their homology to channels first isolated fromDrosophila: the Kv1, or Shaker-related subfamily; the Kv2, orShab-related subfamily; the Kv3, or Shaw-related subfamily; and the Kv4,or Shal-related subfamily. Kv4.2 and Kv4.3 are examples of Kv channelα-subunits of the Shal-related subfamily. Kv4.3 has a uniqueneuroanatomical distribution in that its mRNA is highly expressed inbrainstem monoaminergic and forebrain cholinergic neurons, where it isinvolved in the release of the neurotransmitters dopamine,norepinephrine, serotonin, and acetylcholine. This channel is alsohighly expressed in cortical pyramidal cells and in interneurons.(Serdio P. et al. (1996) J. Neurophys 75:2174-2179). Interestingly, theKv4.3 polypeptide is highly expressed in neurons which express thecorresponding mRNA. The Kv4.3 polypeptide is expressed in thesomatodendritic membranes of these cells, where it is thought tocontribute to the rapidly inactivating K+ conductance. Kv4.2 mRNA iswidely expressed in brain, and the corresponding polypeptide alsoappears to be concentrated in somatodendritic membranes where it alsocontributes to the rapidly inactivating K⁺ conductance (Sheng etal.(1992) Neuron 9:271-84). These somatodendritic A-type Kv channels,like Kv4.2 and Kv4.3 are likely involved in processes which underlielearning and memory, such as integration of sub-threshold synapticresponses and the conductance of back-propagating action potentials(Hoffinan D. A. et al. (1997) Nature 387:869-875).

[0007] Thus, proteins which interact with and modulate the activity ofpotassium channel proteins e.g., potassium channels having a Kv4.2 orKv4.3 subunit, provide novel molecular targets to modulate neuronalexcitability, e.g., action potential conduction, somatodendriticexcitability and neurotransmitter release, in cells expressing thesechannels. In addition, detection of genetic lesions in the gene encodingthese proteins could be used to diagnose and treat cardiovasculardisorders such as heart failure, hypertension, atrial fibrillation,dilated cardiomyopathy, idiopathic cardiomyopathy, or angina.

SUMMARY OF THE INVENTION

[0008] The present invention is based, at least in part, on thediscovery of novel nucleic acid molecules which encode gene productsthat interact with potassium channel proteins or possess substantialhomology to the gene products of the invention that interact withpotassium channel proteins (paralogs). Potassium channel proteins are,for example, potassium channels having a Kv4.2 or Kv4.3 subunit. Thenucleic acid molecules of the invention and their gene products arereferred to herein as “Potassium Channel Interacting Proteins”, “PCIP”,or “KChIP” nucleic acid and protein molecules. The PCIP molecules of thepresent invention are useful as modulating agents to regulate a varietyof cellular processes, in particular, cardiac cell processes.

[0009] Accordingly, in one aspect, this invention provides a method foridentifying a compound suitable for treating a cardiovascular disorder,e.g., arteriosclerosis, ischemia reperfusion injury, restenosis,arterial inflammation, vascular wall remodeling, ventricular remodeling,rapid ventricular pacing, coronary microembolism, tachycardia,bradycardia, pressure overload, aortic bending, coronary arteryligation, vascular heart disease, atrial fibrilation or congestive heartfailure, by contacting a PCIP polypeptide or a fragment thereof, or acell expressing a PCIP polypeptide or a fragment thereof with a testcompound and determining whether the PCIP polypeptide or fragmentthereof binds to the test compound, thereby identifying a compoundsuitable for treating a cardiovascular disorder. In a preferredembodiment, the binding of the test compound to the PCIP polypeptide orfragment thereof is detected by direct detection of testcompound/polypeptide binding. In another embodiment, the binding of thetest compound to the PCIP polypeptide or fragment thereof is detected byusing a competition binding assay. In yet another embodiment, thebinding of the test compound to the PCIP polypeptide or fragment thereofis detected by using an assay for PCIP activity.

[0010] In another aspect, the invention features a method foridentifying a compound suitable for treating a cardiovascular disorder,e.g., arteriosclerosis, ischemia reperfusion injury, restenosis,arterial inflammation, vascular wall remodeling, ventricular remodeling,rapid ventricular pacing, coronary microembolism, tachycardia,bradycardia, pressure overload, aortic bending, coronary arteryligation, vascular heart disease, atrial fibrilation or congestive heartfailure, by incubating a cell expressing a potassium channel comprisinga Kv4.3 or Kv4.2 subunit, or a fragment of a potassium channelcomprising a Kv4.3 or Kv4.2 subunit, and a PCIP polypeptide or fragmentthereof, in the presence and absence of a candidate compound; anddetermining whether the presence of the candidate compound modulates theinteraction of the potassium channel or fragment thereof with the PCIPpolypeptide or fragment thereof, thereby identifying a compound suitablefor treating a cardiovascular disorder.

[0011] In yet another aspect, the invention features a method fortreating a cardiovascular disorder by contacting a potassium channelwith an effective amount of a compound that modulates the binding of aPCIP protein to the potassium channel.

[0012] In a further aspect, the invention features a method fordetermining if a subject is at risk for a cardiovascular disorder bydetecting, in a sample of cells from the subject an alteration in a PCIPgene which causes a mutated PCIP polypeptide to be produced, analteration in a PCIP gene which causes abnormal expression of a PCIPpolypeptide, or an alteration in a PCIP gene which causes abnormalprocessing of a PCIP polypeptide.

[0013] In another aspect, the invention features a method foridentifying a subject suffering from a cardiovascular disorder bydetecting, in a sample of cells from the subject an alteration in a PCIPgene which causes a mutated PCIP polypeptide to be produced, analteration in a PCIP gene which causes abnormal expression of a PCIPpolypeptide, or an alteration in a PCIP gene which causes abnormalprocessing of a PCIP polypeptide.

[0014] In a preferred embodiment, the cardiovascular disorder isassociated with an abnormal I_(to) current.

[0015] Other features and advantages of the invention will be apparentfrom the following detailed description and claims.

BRIEF DESCRIPTION OF THE DRAWINGS

[0016]FIG. 1 depicts the cDNA sequence and predicted amino acid sequenceof human 1v. The nucleotide sequence corresponds to nucleic acids 1 to1463 of SEQ ID NO:1. The amino acid sequence corresponds to amino acids1 to 216 of SEQ ID NO:2.

[0017]FIG. 2 depicts the cDNA sequence and predicted amino acid sequenceof rat 1v. The nucleotide sequence corresponds to nucleic acids 1 to1856 of SEQ ID NO:3. The amino acid sequence corresponds to amino acids1 to 245 of SEQ ID NO:4.

[0018]FIG. 3 depicts the cDNA sequence and predicted amino acid sequenceof mouse 1v. The nucleotide sequence corresponds to nucleic acids 1 to1907 of SEQ ID NO:5. The amino acid sequence corresponds to amino acids1 to 216 of SEQ ID NO:6.

[0019]FIG. 4 depicts the cDNA sequence and predicted amino acid sequenceof rat 1vl. The nucleotide sequence corresponds to nucleic acids 1 to1534 of SEQ ID NO:7. The amino acid sequence corresponds to amino acids1 to 227 of SEQ ID NO:8.

[0020]FIG. 5 depicts the cDNA sequence and predicted amino acid sequenceof mouse 1vl. The nucleotide sequence corresponds to nucleic acids 1 to1540 of SEQ ID NO:9. The amino acid sequence corresponds to amino acids1 to 227 of SEQ ID NO:10.

[0021]FIG. 6 depicts the cDNA sequence and predicted amino acid sequenceof rat 1vn. The nucleotide sequence corresponds to nucleic acids 1 to955 of SEQ ID NO:11. The amino acid sequence corresponds to amino acids1 to 203 of SEQ ID NO:12.

[0022]FIG. 7 depicts the cDNA sequence and predicted amino acid sequenceof human 9ql. The nucleotide sequence corresponds to nucleic acids 1 to2009 of SEQ ID NO:13. The amino acid sequence corresponds to amino acids1 to 270 of SEQ ID NO:14.

[0023]FIG. 8 depicts the cDNA sequence and predicted amino acid sequenceof rat 9ql. The nucleotide sequence corresponds to nucleic acids 1 to1247 of SEQ ID NO:15. The amino acid sequence corresponds to amino acids1 to 257 of SEQ ID NO:16.

[0024]FIG. 9 depicts the cDNA sequence and predicted amino acid sequenceof mouse 9ql. The nucleotide sequence corresponds to nucleic acids 1 to2343 of SEQ ID NO:17. The amino acid sequence corresponds to amino acids1 to 270 of SEQ ID NO:18.

[0025]FIG. 10 depicts the cDNA sequence and predicted amino acidsequence of human 9qm. The nucleotide sequence corresponds to nucleicacids 1 to 1955 of SEQ ID NO:19. The amino acid sequence corresponds toamino acids 1 to 252 of SEQ ID NO:20.

[0026]FIG. 11 depicts the cDNA sequence and predicted amino acidsequence of rat 9qm. The nucleotide sequence corresponds to nucleicacids 1 to 2300 of SEQ ID NO:21. The amino acid sequence corresponds toamino acids 1 to 252 of SEQ ID NO:22.

[0027]FIG. 12 depicts the cDNA sequence and predicted amino acidsequence of human 9qs. The nucleotide sequence corresponds to nucleicacids 1 to 1859 of SEQ ID NO:23. The amino acid sequence corresponds toamino acids 1 to 220 of SEQ ID NO:24.

[0028]FIG. 13 depicts the cDNA sequence and predicted amino acidsequence of monkey 9qs. The nucleotide sequence corresponds to nucleicacids 1 to 2191 of SEQ ID NO:25. The amino acid sequence corresponds toamino acids 1 to 220 of SEQ ID NO:26.

[0029]FIG. 14 depicts the cDNA sequence and predicted amino acidsequence of rat 9qc. The nucleotide sequence corresponds to nucleicacids 1 to 2057 of SEQ ID NO:27. The amino acid sequence corresponds toamino acids 1 to 252 of SEQ ID NO:28.

[0030]FIG. 15 depicts the cDNA sequence and predicted amino acidsequence of rat 8t. The nucleotide sequence corresponds to nucleic acids1 to 1904 of SEQ ID NO:29. The amino acid sequence corresponds to aminoacids 1 to 225 of SEQ ID NO:30.

[0031]FIG. 16 depicts the cDNA sequence and predicted amino acidsequence of human p19. The nucleotide sequence corresponds to nucleicacids 1 to 619 of SEQ ID NO:31. The amino acid sequence corresponds toamino acids 1 to 200 of SEQ ID NO:32.

[0032]FIG. 17 depicts the cDNA sequence and predicted amino acidsequence of rat p19 The nucleotide sequence corresponds to nucleic acids1 to 442 of SEQ ID NO:33. The amino acid sequence corresponds to aminoacids 1 to 109 of SEQ ID NO:34.

[0033]FIG. 18 depicts the cDNA sequence and predicted amino acidsequence of mouse p19. The nucleotide sequence corresponds to nucleicacids 1 to 2644 of SEQ ID NO:35. The amino acid sequence corresponds toamino acids 1 to 256 of SEQ ID NO:36.

[0034]FIG. 19 depicts the cDNA sequence and predicted amino acidsequence of human W28559. The nucleotide sequence corresponds to nucleicacids 1 to 380 of SEQ ID NO:37. The amino acid sequence corresponds toamino acids 1 to 126 of SEQ ID NO:38.

[0035]FIG. 20 depicts the cDNA sequence and predicted amino acidsequence of human P193. The nucleotide sequence corresponds to nucleicacids 1 to 2176 of SEQ ID NO:39. The amino acid sequence corresponds toamino acids 1 to 41 of SEQ ID NO:40.

[0036]FIG. 21 depicts a schematic representation of the rat 1v, the rat9qm, and the mouse P19 proteins, aligned to indicate the conserveddomains among these proteins.

[0037]FIG. 22 depicts the genomic DNA sequence of human 9q.

[0038]FIG. 22A depicts exon 1 and its flanking intron sequences (SEQ IDNO:46).

[0039]FIG. 22B depicts exons 2-11 and the flanking intron sequences (SEQID NO:47).

[0040]FIG. 23 depicts the cDNA sequence and predicted amino acidsequence of monkey KChIP4a. The nucleotide sequence corresponds tonucleic acids 1 to 2413 of SEQ ID NO:48. The amino acid sequencecorresponds to amino acids 1 to 233 of SEQ ID NO:49.

[0041]FIG. 24 depicts the cDNA sequence and predicted amino acidsequence of monkey KChIP4b. The nucleotide sequence corresponds tonucleic acids 1 to 1591 of SEQ ID NO:50. The amino acid sequencecorresponds to amino acids 1 to 233 of SEQ ID NO:51.

[0042]FIG. 25 depicts an alignment of KChIP4a, KchIP4b, 9ql, 1v, p19,and related human paralog (hsncspara) W28559. Amino acids identical tothe consensus are shaded in black, conserved amino acids are shaded ingray.

[0043]FIG. 26 depicts the cDNA sequence and predicted amino acidsequence of rat 33b07. The nucleotide sequence corresponds to nucleicacids 1 to 2051 of SEQ ID NO:52. The amino acid sequence corresponds toamino acids 1 to 407 of SEQ ID NO:53.

[0044]FIG. 27 depicts the cDNA sequence and predicted amino acidsequence of human 33b07. The nucleotide sequence corresponds to nucleicacids 1 to 4148 of SEQ ID NO:54. The amino acid sequence corresponds toamino acids 1 to 414 of SEQ ID NO:55.

[0045]FIG. 28 depicts the cDNA sequence and predicted amino acidsequence of rat 1p. The nucleotide sequence corresponds to nucleic acids1 to 2643 of SEQ ID NO:56. The amino acid sequence corresponds to aminoacids 1 to 267 of SEQ ID NO:57.

[0046]FIG. 29 depicts the cDNA sequence and predicted amino acidsequence of rat 7s. The nucleotide sequence corresponds to nucleic acids1 to 2929 of SEQ ID NO:58. The amino acid sequence corresponds to aminoacids 1 to 270 of SEQ ID NO:59.

[0047]FIG. 30 depicts the cDNA sequence and predicted amino acidsequence of rat 29x. The nucleotide sequence corresponds to nucleicacids 1 to 1489 of SEQ ID NO:60. The amino acid sequence corresponds toamino acids 1 to 351 of SEQ ID NO:61.

[0048]FIG. 31 depicts the cDNA sequence of rat 25r. The nucleotidesequence corresponds to nucleic acids 1 to 1194 of SEQ ID NO:62.

[0049]FIG. 32 depicts the cDNA sequence and predicted amino acidsequence of rat 5p. The nucleotide sequence corresponds to nucleic acids1 to 600 of SEQ ID NO:63. The amino acid sequence corresponds to aminoacids 1 to 95 of SEQ ID NO:64.

[0050]FIG. 33 depicts the cDNA sequence and predicted amino acidsequence of rat 7q. The nucleotide sequence corresponds to nucleic acids1 to 639 of SEQ ID NO:65. The amino acid sequence corresponds to aminoacids 1 to 212 of SEQ ID NO:66.

[0051]FIG. 34 depicts the cDNA sequence and predicted amino acidsequence of rat 19r. The nucleotide sequence corresponds to nucleicacids 1 to 816 of SEQ ID NO:67. The amino acid sequence corresponds toamino acids 1 to 271 of SEQ ID NO:68.

[0052]FIG. 35 depicts the cDNA sequence and predicted amino acidsequence of monkey KChIP4c. The nucleotide sequence corresponds tonucleic acids 1 to 2263 of SEQ ID NO:69. The amino acid sequencecorresponds to amino acids 1 to 229 of SEQ ID NO:70.

[0053]FIG. 36 depicts the cDNA sequence and predicted amino acidsequence of monkey KChIP4d. The nucleotide sequence corresponds tonucleic acids 1 to 2259 of SEQ ID NO:71. The amino acid sequencecorresponds to amino acids 1 to 250 of SEQ ID NO:72.

[0054]FIG. 37 depicts an alignment of KChIP4a, KChIP4b, KChIP4c, andKChIP4d.

[0055]FIG. 38 depicts a graph showing the current traces from CHO cellswhich express Kv4.2 with or without KChIP2 (9ql). Cells are voltageclamped at −80 mV and stepped from −60 mV to +50 mV for 200 ms. Peakcurrent amplitudes at the various test voltages are shown in the rightpanel. FIG. 38 further depicts a table showing the amplitude and kineticeffects of KChIP2 (9ql) on Kv4.2. KchIP2 expression alters the peakcurrent amplitude, inactivation and recovery from inactivation timeconstants, and activation V_(½).

[0056]FIG. 39 depicts a graph showing the current traces from CHO cellswhich express Kv4.2 with or without KChIP3 (p19). Cells are voltageclamped at −80 mV and stepped from −60 mV to +50 mV for 200 ms. Peakcurrent amplitudes at the various test voltages are shown in the rightpanel. FIG. 39 further depicts a table showing the amplitude and kineticeffects of KchIP3 (p19) on Kv4.2. KchIP3 causes alterations in peakcurrent and inactivation and recovery from inactivation time constants.

DETAILED DESCRIPTION OF THE INVENTION

[0057] I. Screening Assays 16 II. Predictive Medicine 23 1. DiagnosticAssays 23 2. Prognostic Assays 25 3. Monitoring of Effects DuringClinical Trials 30 III. Methods of Treatment 31 1. Prophylactic Methods31 2. Therapeutic Methods 32 3. Pharmacogenomics 38

[0058] The present invention is based, at least in part, on thediscovery of novel nucleic acid molecules which encode gene productsthat interact with potassium channel proteins or possess substantialhomology to the gene products of the invention that interact withpotassium channel proteins (paralogs). Potassium channel proteins are,for example, potassium channels having a Kv4.2 or Kv4.3 subunit. Thenucleic acid molecules of the invention and their gene products arereferred to herein as “Potassium Channel Interacting Proteins” “PCIP”,or “KChIP4” nucleic acid and protein molecules. The PCIP proteins of thepresent invention bind to and modulate a potassium channel mediatedactivity in a cell, e.g., a cardiac cell. Kv4 potassium channels, e.g.,potassium channels having a Kv4.2 or Kv4.3 subunit, underlie thevoltage-gated K⁺ current known as I_(to) (transient outward current) inthe mammalian heart (Kaab S. et al (1998) Circulation 98(14):1383-93;Dixon J. E. et al. (1996) Circulation Research 79(4):659-68; Nerbonne JM (1998) Journal of Neurobiology 37(1):37-59; Barry D. M. et al. (1998)Circulation Research 83(5):560-7; Barry D. M. et al. (1996) AnnualReview of Physiology 58:363-94. This current underlies the rapidrepolarization of cardiac myocytes during an action potential. It alsoparticipates in the inter-beat interval by controlling the rate at whichcardiac myocytes reach the threshold for firing a subsequent actionpotential.

[0059] This current is also known to be down regulated in patients withcardiac hypertrophy, resulting in prolongation of the cardiac actionpotential. In these patients, action potential prolongation is thoughtto produce changes in calcium load and calcium handling within themyocardium, which contributes to the progression of cardiac disease fromhypertrophy to heart failure (Wickenden et al. (1998) CardiovascularResearch 37:312). Interestingly, sever PCIPs of the present invention(e.g., 9ql, 9qm, 9qs, shown in SEQ ID NOs:13, 15, 17, 19, 21, 23, and25) bind to and modulate potassium channels containing a Kv4.2 or Kv4.3subunit and contain calcium binding EF-hand domains. Because mutationsin these PCIP genes, defects in the expression of these calcium-bindingPCIP proteins themselves, or defects in the interaction between thesePCIPs and Kv4.2 or Kv4.3 channels, might be expected to lead todecreases in KV4.3 or Kv4.3(I_(m)) currents in the myocardium,therapeutic agents that alter PCIP expression or modulate theinteraction between these PCIPs and Kv4.2 or Kv4.3 may be extremelyvaluable agents to slow or prevent the progression of disease fromhypertrophy to heart failure.

[0060] Accordingly, in one aspect, this invention provides a method foridentifying a compound suitable for treating a cardiovascular disorderby contacting a PCIP polypeptide, or a cell expressing a PCIPpolypeptide with a test compound and determining whether the PCIPpolypeptide binds to the test compound, thereby identifying a compoundsuitable for treating a potassium channel associated disorder such as acardiovascular disorder. As used herein, a “potassium channel associateddisorder” includes a disorder, disease or condition which ischaracterized by a misregulation of a potassium channel mediatedactivity. Potassium channel associated disorders can, for example,detrimentally affect the generation and distribution of electricalimpulses that stimulate the cardiac muscle fibers to contract. Examplesof potassium channel associated disorders include cardiovasculardisorders such as arteriosclerosis, ischemia reperfusion injury,restenosis, arterial inflammation, vascular wall remodeling, ventricularremodeling, rapid ventricular pacing, coronary microembolism,tachycardia, bradycardia, pressure overload, aortic bending, coronaryartery ligation, vascular heart disease, atrial fibrilation, long-QTsyndrome, congestive heart failure, sinus node disfunction, angina,heart failure, hypertension, atrial fibrillation, atrial flutter,dilated cardiomyopathy, idiopathic cardiomyopathy, myocardialinfarction, coronary artery disease, coronary artery spasm, orarrhythmia. In a preferred embodiment, the cardiovascular disorder isassociated with an abnormal I_(to) current.

[0061] In a preferred embodiment, the binding of the test compound tothe PCIP polypeptide is detected by direct detection of testcompound/polypeptide binding. In another embodiment, the binding of thetest compound to the PCIP polypeptide is detected by using a competitionbinding assay. In yet another embodiment, the binding of the testcompound to the PCIP polypeptide is detected by using an assay for PCIPactivity. As used interchangeably herein, a “PCIP activity”, “biologicalactivity of PCIP” or “functional activity of PCIP”, refers to anactivity exerted by a PCIP protein, polypeptide or nucleic acid moleculeon a PCIP responsive cell or on a PCIP protein substrate, as determinedin vivo, or in vitro, according to standard techniques. In oneembodiment, a PCIP activity is a direct activity, such as an associationwith a PCIP-target molecule. As used herein, a “target molecule” or“binding partner” is a molecule with which a PCIP protein binds orinteracts in nature, such that PCIP-mediated function is achieved. APCIP target molecule can be a non-PCIP molecule or a PCIP protein orpolypeptide. In an exemplary embodiment, a PCIP target molecule is aPCIP ligand. Alternatively, a PCIP activity is an indirect activity,such as a cellular signaling activity mediated by interaction of thePCIP protein with a PCIP ligand.

[0062] The biological activities of PCIP are described herein. Forexample, the binding of the test compound to the PCIP polypeptide isdetected by using an assay for one or more of the following activities:(1) interaction with (e.g., binding to) a potassium channel protein orportion thereof, e.g., a potassium channel comprising a Kv4.3 or Kv4.2subunit; (2) regulation of the phosphorylation state of a potassiumchannel protein or portion thereof, (3) association with (e.g., bindingto) calcium and acting as a calcium dependent kinase; (4) modulation ofa potassium channel mediated activity in a cell (e.g., a cardiac cellsuch as a pericardial cell, a myocardial cell, or an endocardial cell);(5) modulation of chromatin formation in a cell, e.g., a cardiac cell;(6) modulation of vesicular traffic and protein transport in a cell,e.g., a cardiac cell; (7) modulation of cytokine signaling in a cell,e.g., a cardiac cell; (8) regulation of the association of a potassiumchannel protein or portion thereof with the cellular cytoskeleton; (9)modulation of cellular proliferation; (10) modulation of the release ofneurotransmitters; (11) modulation of membrane excitability; (12)influencing the resting potential of membranes; (13) modulation of waveforms and frequencies of action potentials; and (14) modulation ofthresholds of excitation.

[0063] In another aspect, the invention features a method foridentifying a compound suitable for treating a cardiovascular disorderby incubating a cell expressing a potassium channel or a fragmentthereof, and a PCIP polypeptide, in the presence and absence of acandidate compound; and determining whether the presence of thecandidate compound modulates the interaction of the potassium channel orfragment thereof with the PCIP polypeptide, thereby identifying acompound suitable for treating a cardiovascular disorder. As usedherein, a “potassium channel” includes a protein or polypeptide that isinvolved in receiving, conducting, and transmitting signals in anexcitable cell. Potassium channels are typically expressed inelectrically excitable cells, e.g., neurons, cardiac, skeletal andsmooth muscle, renal, endocrine, and egg cells, and can formheteromultimeric structures, e.g., composed of pore-forming andcytoplasmic subunits. Examples of potassium channels include: (1) thevoltage-gated potassium channels, (2) the ligand-gated potassiumchannels, and (3) the mechanically-gated potassium channels. For adetailed description of potassium channels, see Kandel E. R. et al.,Principles of Neural Science, second edition, (Elsevier SciencePublishing Co., Inc., N.Y. (1985)), the contents of which areincorporated herein by reference. The PCIP proteins of the presentinvention have been shown to interact with, for example, potassiumchannels having a Kv4.3 subunit or a Kv4.2 subunit.

[0064] In yet another aspect, the invention features a method fortreating a cardiovascular disorder by contacting a potassium channelwith an effective amount of a compound that modulates the binding of aPCIP protein to the potassium channel.

[0065] In a further aspect, the invention features a method fordetermining if a subject is at risk for a cardiovascular disorder bydetecting, in a sample of cells from the subject an alteration in a PCIPgene which causes a mutated PCIP polypeptide to be produced, analteration in a PCIP gene which causes abnormal expression of a PCIPpolypeptide, or an alteration in a PCIP gene which causes abnormalprocessing of a PCIP polypeptide.

[0066] In another aspect, the invention features a method foridentifying a subject suffering from a cardiovascular disorder bydetecting, in a sample of cells from the subject an alteration in a PCIPgene which causes a mutated PCIP polypeptide to be produced, analteration in a PCIP gene which causes abnormal expression of a PCIPpolypeptide, or an alteration in a PCIP gene which causes abnormalprocessing of a PCIP polypeptide.

[0067] The PCIP molecules of the present invention were initiallyidentified based on their ability, as determined using yeast two-hybridassays (described in detail in Example 1), to interact with theamino-terminal 180 amino acids of rat Kv4.3 subunit. Further bindingstudies with other potassium subunits were performed to demonstratespecificity of the PCIP for Kv4.3 and Kv4.2. In situ localization,immuno-histochemical methods, co-immunoprecipitation and patch clampingmethods were then used to clearly demonstrate that the PCIPs of thepresent invention interact with and modulate the activity of potassiumchannels, particularly those comprising a 4.3 or 4.2 subunit.

[0068] Several novel human, mouse, monkey, and rat PCIP family membershave been identified, referred to herein as 1v, 9q, p19, W28559, KChIP4,33b07, 1p, and rat 7s proteins and nucleic acid molecules. The human,rat, and mouse cDNAs encoding the 1v polypeptide are represented by SEQID NOs:1, 3, and 5, and shown in FIGS. 1, 2, and 3, respectively. In thebrain, 1v mRNA is highly expressed in neocortical and hippocampalinterneurons, in the thalamic reticular nucleus and medial habenula, inbasal forebrain and striatal cholinergic neurons, in the superiorcolliculus, and in cerebellar granule cells. The 1v polypeptide ishighly expressed in the somata, dendrites, axons and axon terminals ofcells that express 1v mRNA. Splice variants of the 1v gene have beenidentified in rat and mouse and are represented by SEQ ID NOs:7, 9, and11 and shown in FIGS. 4, 5, and 6, respectively. 1v polypeptideinteracts with potassium channels comprising Kv4.3 or Kv4.2 subunits,but not with Kv1.1 subunits. As determined by Northern blot, the 1vtranscripts (mRNA) are expressed predominantly in the brain.

[0069] The 8t cDNA (SEQ ID NO:29) encodes a polypeptide having amolecular weight of approximately 26 kD corresponding to SEQ ID NO:30(see FIG. 15). The 8t polypeptide interacts with potassium channelcomprising Kv4.3 or Kv4.2 subunits, but not with Kv1.1 subunits. Asdetermined by Northern blot and in situ data, the 8t mRNA is expressedpredominantly in the heart and the brain. The 8t cDNA is a splicevariant of 9q.

[0070] Human, rat, monkey, and mouse 9q cDNA was also isolated. Splicevariants include human 9ql (SEQ ID NO:13; FIG. 7) rat 9ql (SEQ ID NO:15;FIG. 8), mouse 9ql (SEQ ID NO:17; FIG. 9), human 9qm (SEQ ID NO:19; FIG.10), rat 9qm (SEQ ID NO:21; FIG. 11), human 9qs (SEQ ID NO:23; FIG. 12),monkey 9qs (SEQ ID NO:25; FIG. 13), and rat 9qc (SEQ ID NO:27; FIG. 14).The genomic DNA sequence of 9q has also be determined. Exon 1 and itsflanking intron sequences (SEQ ID NO:46) are shown in FIG. 22A. Exons2-11 and the flanking intron sequences (SEQ ID NO:47) are shown in FIG.22B. 9q polypeptides interact with potassium channels comprising Kv4.3or Kv4.2 subunits, but not with Kv1.1 subunits. As determined byNorthern blot and in situ data, the 9q proteins are expressedpredominantly in the heart and the brain. In the brain, 9q mRNA ishighly expressed in the neostriatum, hippocampal formation, neocorticalpyramidal cells and intemeurons, and in the thalamus, superiorcolliculus, and cerebellum.

[0071] Human, rat, and mouse P19 cDNA were also isolated. Human P19 isshown in SEQ ID NO:31 and FIG. 16; and in SEQ ID NO:39 and FIG. 20 (the3′ sequence). Rat P19 is shown in SEQ ID NO:33 and FIG. 17, and mouseP19 is shown in SEQ ID NO:35 and FIG. 18. P19 polypeptides interact withpotassium channels comprising Kv4.3 or Kv4.2 subunits, but not withKv1.1 subunits. As determined by northern blot analysis, the P19transcripts (mRNA) are expressed predominantly in the brain and to amuch lesser degree in the heart.

[0072] A partial human paralog of the PCIP molecules was alsoidentified. This paralog is referred to herein as W28559 and is shown inSEQ ID NO:37 and FIG. 19.

[0073] Monkey KChIP4a and its splice variants KChIP4b, KChIP4c, andKChIP4d were also identified. Monkey KChIP4a is shown in SEQ ID NO:48and FIG. 23. Monkey KChIP4b is shown in SEQ ID NO:50 and FIG. 24. MonkeyKChIP4c is shown in SEQ ID NO:69 and FIG. 35. Monkey KChIP4d is shown inSEQ ID NO:71 and FIG. 36.

[0074] The nucleotide sequence of the full length rat 33b07 cDNA and thepredicted amino acid sequence of the rat 33b07 polypeptide are shown inFIG. 26 and in SEQ ID NOs:52 and 53, respectively. The rat 33b07 cDNAencodes a protein having a molecular weight of approximately 44.7 kD andwhich is 407 amino acid residues in length. Rat 33b07 binds rKv4.3N andrKv4.2N with slight preference for rKv4.2N in yeast 2-hybrid assays.

[0075] The nucleotide sequence of the full length human 33b07 cDNA andthe predicted amino acid sequence of the human 33b07 polypeptide areshown in FIG. 27 and in SEQ ID NOs:54 and 55, respectively.

[0076] The nucleotide sequence of the partial length rat 1p cDNA and thepredicted amino acid sequence of the rat 1p polypeptide are shown inFIG. 28 and in SEQ ID NOs:56 and 57, respectively. The rat 1p cDNAencodes a protein having a molecular weight of approximately 28.6 kD andwhich is 267 amino acid residues in length. Rat 1p binds rKv4.3N andrKv4.2N with slight preference for rKv4.3N in yeast two-hybrid assays.

[0077] The nucleotide sequence of the partial length rat 7s cDNA and thepredicted amino acid sequence of the rat 7s polypeptide are shown inFIG. 29 and in SEQ ID NOs:58 and 59, respectively. The rat 7s cDNAencodes a protein having a molecular weight of approximately 28.6 kD andwhich is 270 amino acid residues in length. Rat 7s binds rKv4.3N andrKv4.2N with preference for rKv4.3N in yeast two-hybrid assays.

[0078] The sequences of the PCIP molecules used in the methods of thepresent invention are summarized below, in Tables I and II. TABLE I PCIPMolecules Used in the Methods of the Present Invention SEQ SEQ NucleicAcid ID NO: ID NO: PCIP Molecule Form Source DNA PROTEIN ATCC 1v 1vhuman  1  2 98994 (225-875)* 1v rat  3  4 98946 (210-860) 1v mouse  5  698945 (477-1127) 1vl rat  7  8 98942 (31-714) 1vl mouse  9 10 98943(77-760) 1vn rat 11 12 98944 (partial) (345-955) 9q Genomic DNA human 46sequence (Exon 1 and flanking intron sequences) Genomic DNA human 47sequence (Exons 2-11 and flanking intron sequences) 9ql human 13 1498993 (207-1019) 98991 9ql rat (2-775) 15 16 98948 (partial) 9ql mouse17 18 98937 (181-993) 9qm human 19 20 98993 (207-965) 98991 9qm rat 2122 98941 (214-972) 9qs human 23 24 98951 (207-869) 9qs monkey 25 2698950 (133-795) 9qc rat 27 28 98947 (208-966) 8t rat 29 30 98939(partial) (1-678) p19 p19 Human 31 32 (1-771) p19 rat 33 34 98936(partial) (1-330) p19 mouse 35 36 98940 (49-819) p193 Human 39 40 98949(partial) (2-127) W28559 W28559 human 37 38 (partial) (1-339) KChIP4KChIP4a Monkey 48 49 (265-966) KChIP4b Monkey 50 51 C-terminal (265-966)splice variant KChIP4c Monkey 69 70 splice variant (122-811) KChIP4dMonkey 71 72 splice variant (64-816)

[0079] TABLE II PCIP Molecules Used in the Methods of the PresentInvention SEQ SEQ Nucleic Acid ID NO: ID NO: PCIP Molecule Form SourceDNA PROTEIN ATCC 33b07 33b07 Human 52 53 Novel (88-1332) 33b07 Rat 54 55(85-1308) 1p 1p Rat 56 57 Novel (partial) (1-804) 7s 7s Rat 58 59 Novel(partial) (1-813) 29x 29x Rat 60 61 (433-1071) 25r Rat 62 splice variant(130-768) of 29x 5p 5p Rat 63 64 (52-339) 7q 7q Rat 65 66 (1-639) 19r19r Rat 67 68 (1-816)

[0080] Plasmids containing the nucleotide sequences encoding human, ratand monkey PCIPs were deposited with American Type Culture Collection(ATCC), 10801 University Boulevard, Manassas, Va. 20110-2209, on Nov.17, 1998, and assigned the Accession Numbers described above. Thesedeposits will be maintained under the terms of the Budapest Treaty onthe International Recognition of the Deposit of Microorganisms for thePurposes of Patent Procedure. These deposits were made merely as aconvenience for those of skill in the art and are not an admission thata deposit is required under 35 U.S.C. §112.

[0081] Clones containing cDNA molecules encoding human p19 (cloneEphP19) and human 33b07 (clone Eph33b07) were deposited with AmericanType Culture Collection (Manassas, Va.) on Jul. 8, 1998 as AccessionNumber ______, as part of a composite deposit representing a mixture oftwo strains, each carrying one recombinant plasmid harboring aparticular cDNA clone. (The ATCC strain designation for the mixture ofhP19 and h33b07 is EphP19h33b07mix).

[0082] To distinguish the strains and isolate a strain harboring aparticular cDNA clone, an aliquot of the mixture can be streaked out tosingle colonies on LB plates supplemented with 100 ug/ml ampicillin,single colonies grown, and then plasmid DNA extracted using a standardminipreparation procedure. Next, a sample of the DNA minipreparation canbe digested with NotI and the resultant products resolved on a 0.8%agarose gel using standard DNA electrophoresis conditions. The digestgives the following band patterns: EphP19: 7 kb 9 (single band),Eph33b07: 5.8 kb (single band).

[0083] Various aspects of the invention are described in further detailin the following subsections:

[0084] I. Screening Assays:

[0085] The invention provides a method (also referred to herein as a“screening assay”) for identifying modulators, i.e., candidate or testcompounds or agents (e.g., peptides, peptidomimetics, small molecules orother drugs) which bind to PCIP proteins, have a stimulatory orinhibitory effect on, for example, PCIP expression or PCIP activity, orhave a stimulatory or inhibitory effect on, for example, the expressionor activity of a PCIP substrate.

[0086] In one embodiment, the invention provides assays for screeningcandidate or test compounds which are substrates of a PCIP protein orpolypeptide or biologically active portion thereof. In anotherembodiment, the invention provides assays for screening candidate ortest compounds which bind to or modulate the activity of a PCIP proteinor polypeptide or biologically active portion thereof. The testcompounds of the present invention can be obtained using any of thenumerous approaches in combinatorial library methods known in the art,including: biological libraries; spatially addressable parallel solidphase or solution phase libraries; synthetic library methods requiringdeconvolution; the ‘one-bead one-compound’ library method; and syntheticlibrary methods using affinity chromatography selection. The biologicallibrary approach is limited to peptide libraries, while the other fourapproaches are applicable to peptide, non-peptide oligomer or smallmolecule libraries of compounds (Lam, K. S. (1997) Anticancer Drug Des.12:145).

[0087] Examples of methods for the synthesis of molecular libraries canbe found in the art, for example in: DeWitt et al. (1993) Proc. Natl.Acad. Sci. U.S.A. 90:6909; Erb et al. (1994) Proc. Natl. Acad. Sci. USA91:11422; Zuckermann et al. (1994). J. Med. Chem. 37:2678; Cho et al.(1993) Science 261:1303; Carrell et al. (1994) Angew. Chem. Int. Ed.Engl. 33:2059; Carell et al. (1994) Angew. Chem. Int. Ed. Engl. 33:2061;and in Gallop et al. (1994) J. Med. Chem. 37:1233.

[0088] Libraries of compounds may be presented in solution (e.g.,Houghten (1992) Biotechniques 13:412-421), or on beads (Lam (1991)Nature 354:82-84), chips (Fodor (1993) Nature 364:555-556), bacteria(Ladner U.S. Pat. No. 5,223,409), spores (Ladner USP '409), plasmids(Cull et al. (1992) Proc Natl Acad Sci USA 89:1865-1869) or on phage(Scott and Smith (1990) Science 249:386-390); (Devlin (1990) Science249:404-406); (Cwirla et al. (1990) Proc. Natl. Acad. Sci.87:6378-6382); (Felici (1991) J. Mol. Biol. 222:301-310); (Ladnersupra.).

[0089] In one embodiment, an assay is a cell-based assay in which a cellwhich expresses a PCIP protein or biologically active portion thereof iscontacted with a test compound and the ability of the test compound tomodulate PCIP activity, e.g., binding to a potassium channel comprisinga Kv4.2 or Kv4.2 subunit, or a portion thereof, is determined.Determining the ability of the test compound to modulate PCIP activitycan be accomplished by monitoring, for example, the I_(to) current orthe release of a neurotransmitter from a cell which expresses PCIP suchas a cardiac cell. Currents in cells, e.g., the I_(to) current, can bemeasured using the patch-clamp technique as described in the Examplessection using the techniques described in, for example, Hamill et al.1981. Pfluegers Arch. 391:85-100). The cell, for example, can be ofmammalian origin. Determining the ability of the test compound tomodulate the ability of PCIP to bind to a substrate can be accomplished,for example, by coupling the PCIP substrate with a radioisotope orenzymatic label such that binding of the PCIP substrate to PCIP can bedetermined by detecting the labeled PCIP substrate in a complex. Forexample, compounds (e.g., PCIP substrates) can be labeled with ¹²⁵I,³⁵S, ¹⁴C, or ³H, either directly or indirectly, and the radioisotopedetected by direct counting of radioemmission or by scintillationcounting. Alternatively, compounds can be enzymatically labeled with,for example, horseradish peroxidase, alkaline phosphatase, orluciferase, and the enzymatic label detected by determination ofconversion of an appropriate substrate to product.

[0090] It is also within the scope of this invention to determine theability of a compound (e.g., PCIP substrate) to interact with PCIPwithout the labeling of any of the interactants. For example, amicrophysiometer can be used to detect the interaction of a compoundwith PCIP without the labeling of either the compound or the PCIP.McConnell, H. M. et al. (1992) Science 257:1906-1912. As used herein, a“microphysiometer” (e.g., Cytosensor) is an analytical instrument thatmeasures the rate at which a cell acidifies its environment using alight-addressable potentiometric sensor (LAPS). Changes in thisacidification rate can be used as an indicator of the interactionbetween a compound and PCIP.

[0091] In another embodiment, an assay is a cell-based assay comprisingcontacting a cell expressing a PCIP target molecule (e.g., a potassiumchannel comprising a Kv4.2 or Kv4.2 subunit, or a portion thereof, isdetermined. Determining the ability of the test compound to modulate, ora fragment thereof) with a test compound and determining the ability ofthe test compound to modulate (e.g., stimulate or inhibit) the activityof the PCIP target molecule. Determining the ability of the testcompound to modulate the activity of a PCIP target molecule can beaccomplished, for example, by determining the ability of the PCIPprotein to bind to or interact with the PCIP target molecule, e.g., apotassium channel or a fragment thereof.

[0092] Determining the ability of the PCIP protein or a biologicallyactive fragment thereof, to bind to or interact with a PCIP targetmolecule can be accomplished by one of the methods described above fordetermining direct binding. In a preferred embodiment, determining theability of the PCIP protein to bind to or interact with a PCIP targetmolecule can be accomplished by determining the activity of the targetmolecule. For example, the activity of the target molecule can bedetermined by detecting induction of a cellular second messenger of thetarget (i.e., intracellular Ca²⁺, diacylglycerol, IP₃, and the like),detecting catalytic/enzymatic activity of the target an appropriatesubstrate, detecting the induction of a reporter gene (comprising atarget-responsive regulatory element operatively linked to a nucleicacid encoding a detectable marker, e.g., luciferase), or detecting atarget-regulated cellular response such as the release of aneurotransmitter.

[0093] In yet another embodiment, an assay of the present invention is acell-free assay in which a PCIP protein or biologically active portionthereof is contacted with a test compound and the ability of the testcompound to bind to the PCIP protein or biologically active portionthereof is determined. Preferred biologically active portions of thePCIP proteins to be used in assays of the present invention includefragments which participate in interactions with non-PCIP molecules,e.g., potassium channels comprising a Kv4.2 or Kv4.2 subunit, or aportion thereof, is determined. Determining the ability of the testcompound to modulate, or fragments thereof, or fragments with highsurface probability scores. Binding of the test compound to the PCIPprotein can be determined either directly or indirectly as describedabove. In a preferred embodiment, the assay includes contacting the PCIPprotein or biologically active portion thereof with a known compoundwhich binds PCIP to form an assay mixture, contacting the assay mixturewith a test compound, and determining the ability of the test compoundto interact with a PCIP protein, wherein determining the ability of thetest compound to interact with a PCIP protein comprises determining theability of the test compound to preferentially bind to PCIP orbiologically active portion thereof as compared to the known compound.

[0094] In another embodiment, the assay is a cell-free assay in which aPCIP protein or biologically active portion thereof is contacted with atest compound and the ability of the test compound to modulate (e.g.,stimulate or inhibit) the activity of the PCIP protein or biologicallyactive portion thereof is determined. Determining the ability of thetest compound to modulate the activity of a PCIP protein can beaccomplished, for example, by determining the ability of the PCIPprotein to bind to a PCIP target molecule by one of the methodsdescribed above for determining direct binding. Determining the abilityof the PCIP protein to bind to a PCIP target molecule can also beaccomplished using a technology such as real-time BiomolecularInteraction Analysis (BIA). Sjolander, S. and Urbaniczky, C. (1991)Anal. Chem. 63:2338-2345 and Szabo et al. (1995) Curr. Opin. Struct.Biol. 5:699-705. As used herein, “BIA” is a technology for studyingbiospecific interactions in real time, without labeling any of theinteractants (e.g., BIAcore). Changes in the optical phenomenon ofsurface plasmon resonance (SPR) can be used as an indication ofreal-time reactions between biological molecules.

[0095] In an alternative embodiment, determining the ability of the testcompound to modulate the activity of a PCIP protein can be accomplishedby determining the ability of the PCIP protein to further modulate theactivity of a downstream effector of a PCIP target molecule. Forexample, the activity of the effector molecule on an appropriate targetcan be determined or the binding of the effector to an appropriatetarget can be determined as previously described.

[0096] In yet another embodiment, the cell-free assay involvescontacting a PCIP protein or biologically active portion thereof with aknown compound which binds the PCIP protein to form an assay mixture,contacting the assay mixture with a test compound, and determining theability of the test compound to interact with the PCIP protein, whereindetermining the ability of the test compound to interact with the PCIPprotein comprises determining the ability of the PCIP protein topreferentially bind to or modulate the activity of a PCIP targetmolecule.

[0097] The cell-free assays of the present invention are amenable to useof both soluble and/or membrane-bound forms of isolated proteins. In thecase of cell-free assays in which a membrane-bound form of an isolatedprotein is used (e.g., a potassium channel) it may be desirable toutilize a solubilizing agent such that the membrane-bound form of theisolated protein is maintained in solution. Examples of suchsolubilizing agents include non-ionic detergents such asn-octylglucoside, n-dodecylglucoside, n-dodecylmaltoside,octanoyl-N-methylglucamide, decanoyl-N-methylglucamide, Triton® X-100,Triton® X-1214, Thesit®, Isotridecypoly(ethylene glycol ether)_(n),3-[(3-cholamidopropyl)dimethylamminio]-1-propane sulfonate (CHAPS),3-[(3-cholamidopropyl)dimethylamminio]-2-hydroxy-1-propane sulfonate(CHAPSO), or N-dodecyl=N,N-dimethyl-3-ammonio-1-propane sulfonate.

[0098] In more than one embodiment of the above assay methods of thepresent invention, it may be desirable to immobilize either PCIP or itstarget molecule to facilitate separation of complexed from uncomplexedforms of one or both of the proteins, as well as to accommodateautomation of the assay. Binding of a test compound to a PCIP protein,or interaction of a PCIP protein with a target molecule in the presenceand absence of a candidate compound, can be accomplished in any vesselsuitable for containing the reactants. Examples of such vessels includemicrotitre plates, test tubes, and micro-centrifuge tubes. In oneembodiment, a fusion protein can be provided which adds a domain thatallows one or both of the proteins to be bound to a matrix. For example,glutathione-S-transferase/PCIP fusion proteins orglutathione-S-transferase/target fusion proteins can be adsorbed ontoglutathione sepharose beads (Sigma Chemical, St. Louis, Mo.) orglutathione derivatized microtitre plates, which are then combined withthe test compound or the test compound and either the non-adsorbedtarget protein or PCIP protein, and the mixture incubated underconditions conducive to complex formation (e.g., at physiologicalconditions for salt and pH). Following incubation, the beads ormicrotitre plate wells are washed to remove any unbound components, thematrix immobilized in the case of beads, complex determined eitherdirectly or indirectly, for example, as described above. Alternatively,the complexes can be dissociated from the matrix, and the level of PCIPbinding or activity determined using standard techniques.

[0099] Other techniques for immobilizing proteins on matrices can alsobe used in the screening assays of the invention. For example, either aPCIP protein or a PCIP target molecule can be immobilized utilizingconjugation of biotin and streptavidin. Biotinylated PCIP protein ortarget molecules can be prepared from biotin-NHS (N-hydroxy-succinimide)using techniques known in the art (e.g., biotinylation kit, PierceChemicals, Rockford, Ill.), and immobilized in the wells ofstreptavidin-coated 96 well plates (Pierce Chemical). Alternatively,antibodies reactive with PCIP protein or target molecules but which donot interfere with binding of the PCIP protein to its target moleculecan be derivatized to the wells of the plate, and unbound target or PCIPprotein trapped in the wells by antibody conjugation. Methods fordetecting such complexes, in addition to those described above for theGST-immobilized complexes, include immunodetection of complexes usingantibodies reactive with the PCIP protein or target molecule, as well asenzyme-linked assays which rely on detecting an enzymatic activityassociated with the PCIP protein or target molecule.

[0100] In a preferred embodiment, candidate or test compounds or agentsare tested for their ability to inhibit or stimulate a PCIP molecule'sability to modulate vesicular traffic and protein transport in a cell,e.g., a cardiac cell, using the assays described in, for example, KomadaM. et al. (1999) Genes Dev.13(11):1475-85, and Roth M. G. et al. (1999)Chem. Phys. Lipids. 98(1-2):141-52, the contents of which areincorporated herein by reference.

[0101] In another preferred embodiment, candidate or test compounds oragents are tested for their ability to inhibit or stimulate a PCIPmolecule's ability to regulate the phosphorylation state of a potassiumchannel protein or portion thereof, using for example, an in vitrokinase assay. Briefly, a PCIP target molecule, e.g., animmunoprecipitated potassium channel from a cell line expressing such amolecule, can be incubated with the PCIP protein and radioactive ATP,e.g., [γ-³²P] ATP, in a buffer containing MgCl₂ and MnCl₂, e.g., 10 mMMgCl₂ and 5 mM MnCl₂. Following the incubation, the immunoprecipitatedPCIP target molecule, e.g., the potassium channel, can be separated bySDS-polyacrylamide gel electrophoresis under reducing conditions,transferred to a membrane, e.g., a PVDF membrane, and autoradiographed.The appearance of detectable bands on the autoradiograph indicates thatthe PCIP substrate, e.g., the potassium channel, has beenphosphorylated. Phosphoaminoacid analysis of the phosphorylatedsubstrate can also be performed in order to determine which residues onthe PCIP substrate are phosphorylated. Briefly, the radiophosphorylatedprotein band can be excised from the SDS gel and subjected to partialacid hydrolysis. The products can then be separated by one-dimensionalelectrophoresis and analyzed on, for example, a phosphoimager andcompared to ninhydrin-stained phosphoaminoacid standards. Assays such asthose described in, for example, Tamaskovic R. et al. (1999) Biol. Chem.380(5):569-78, the contents of which are incorporated herein byreference, can also be used.

[0102] In another preferred embodiment, candidate or test compounds oragents are tested for their ability to inhibit or stimulate a PCIPmolecule's ability to associate with (e.g., bind) calcium, using forexample, the assays described in Liu L. (1999) Cell Signal. 11 (5):317-24 and Kawai T. et al. (1999) Oncogene 18(23):3471-80, the contentsof which are incorporated herein by reference.

[0103] In another preferred embodiment, candidate or test compounds oragents are tested for their ability to inhibit or stimulate a PCIPmolecule's ability to modulate chromatin formation in a cell, using forexample, the assays described in Okuwaki M. et al. (1998) J. Biol. Chem.273(51):34511-8 and Miyaji-Yamaguchi M. (1999) J. Mol. Biol.290(2):547-557, the contents of which are incorporated herein byreference.

[0104] In yet another preferred embodiment, candidate or test compoundsor agents are tested for their ability to inhibit or stimulate a PCIPmolecule's ability to modulate cellular proliferation, using forexample, the assays described in Baker F. L. et al. (1995) Cell Prolif.28(1):1-15, Cheviron N. et al. (1996) Cell Prolif. 29(8):437-46, Hu Z.W. et al. (1999) J. Pharmacol. Exp. Ther. 290(1):28-37 and Elliott K. etal. (1999) Oncogene 18(24):3564-73, the contents of which areincorporated herein by reference.

[0105] In a preferred embodiment, candidate or test compounds or agentsare tested for their ability to inhibit or stimulate a PCIP molecule'sability to regulate the association of a potassium channel protein orportion thereof with the cellular cytoskeleton, using for example, theassays described in Gonzalez C. et al. (1998) Cell Mol. Biol.44(7):1117-27and Chia C. P. et al. (1998) Exp. Cell Res.244(1):340-8,the contents of which are incorporated herein by reference.

[0106] In another preferred embodiment, candidate or test compounds oragents are tested for their ability to inhibit or stimulate a PCIPmolecule's ability to modulate membrane excitability, using for example,the assays described in Bar-Sagi D. et al. (1985) J. Biol. Chem.260(8):4740-4 and Barker J. L. et al. (1984) Neurosci. Lett.47(3):313-8, the contents of which are incorporated herein by reference.

[0107] In another preferred embodiment, candidate or test compounds oragents are tested for their ability to inhibit or stimulate a PCIPmolecule's ability to modulate cytokine signaling in a cell, e.g., acardiac cell, the assays described in Nakashima Y. et al. (1999) J. BoneJoint Surg. Am. 81(5):603-15, the contents of which are incorporatedherein by reference.

[0108] In another embodiment, modulators of PCIP expression areidentified in a method wherein a cell is contacted with a candidatecompound and the expression of PCIP mRNA or protein in the cell isdetermined. The level of expression of PCIP mRNA or protein in thepresence of the candidate compound is compared to the level ofexpression of PCIP mRNA or protein in the absence of the candidatecompound. The candidate compound can then be identified as a modulatorof PCIP expression based on this comparison. For example, whenexpression of PCIP mRNA or protein is greater (statisticallysignificantly greater) in the presence of the candidate compound than inits absence, the candidate compound is identified as a stimulator ofPCIP mRNA or protein expression. Alternatively, when expression of PCIPmRNA or protein is less (statistically significantly less) in thepresence of the candidate compound than in its absence, the candidatecompound is identified as an inhibitor of PCIP mRNA or proteinexpression. The level of PCIP mRNA or protein expression in the cellscan be determined by methods described herein for detecting PCIP mRNA orprotein.

[0109] In yet another aspect of the invention, the PCIP proteins can beused as “bait proteins” in a two-hybrid assay or three-hybrid assay(see, e.g., U.S. Pat. No. 5,283,317; Zervos et al. (1993) Cell72:223-232; Madura et al. (1993) J. Biol. Chem. 268:12046-12054; Bartelet al. (1993) Biotechniques 14:920-924; Iwabuchi et al. (1993) Oncogene8:1693-1696; and Brent WO94/10300), to identify other proteins, whichbind to or interact with PCIP (“PCIP-binding proteins” or “PCIP-bp”) andare involved in PCIP activity (described in more detail in the Examplessection below). Such PCIP-binding proteins are also likely to beinvolved in the propagation of signals by the PCIP proteins or PCIPtargets as, for example, downstream elements of a PCIP-mediatedsignaling pathway. Alternatively, such PCIP-binding proteins are likelyto be PCIP inhibitors.

[0110] The two-hybrid system is based on the modular nature of mosttranscription factors, which consist of separable DNA-binding andactivation domains. Briefly, the assay utilizes two different DNAconstructs. In one construct, the gene that codes for a PCIP protein isfused to a gene encoding the DNA binding domain of a known transcriptionfactor (e.g., GAL-4). In the other construct, a DNA sequence, from alibrary of DNA sequences, that encodes an unidentified protein (“prey”or “sample”) is fused to a gene that codes for the activation domain ofthe known transcription factor. If the “bait” and the “prey” proteinsare able to interact, in vivo, forming a PCIP-dependent complex, theDNA-binding and activation domains of the transcription factor arebrought into close proximity. This proximity allows transcription of areporter gene (e.g., LacZ) which is operably linked to a transcriptionalregulatory site responsive to the transcription factor. Expression ofthe reporter gene can be detected and cell colonies containing thefunctional transcription factor can be isolated and used to obtain thecloned gene which encodes the protein which interacts with the PCIPprotein.

[0111] This invention further pertains to novel agents identified by theabove-described screening assays. Accordingly, it is within the scope ofthis invention to further use an agent identified as described herein inan appropriate animal model. For example, an agent identified asdescribed herein (e.g., a PCIP modulating agent, an antisense PCIPnucleic acid molecule, a PCIP-specific antibody, or a PCIP-bindingpartner) can be used in an animal model to determine the efficacy,toxicity, or side effects of treatment with such an agent.Alternatively, an agent identified as described herein can be used in ananimal model to determine the mechanism of action of such an agent.Furthermore, this invention pertains to uses of novel agents identifiedby the above-described screening assays for treatments as describedherein.

[0112] II. Predictive Medicine:

[0113] The present invention also pertains to the field of predictivemedicine in which diagnostic assays, prognostic assays, and monitoringclinical trials are used for prognostic (predictive) purposes to therebytreat an individual prophylactically. Accordingly, one aspect of thepresent invention relates to diagnostic assays for determining PCIPprotein and/or nucleic acid expression as well as PCIP activity, in thecontext of a biological sample (e.g., blood, serum, cells, tissue) tothereby determine whether an individual is afflicted with a disease ordisorder, or is at risk of developing a disorder, associated withaberrant PCIP expression or activity. The invention also provides forprognostic (or predictive) assays for determining whether an individualis at risk of developing a disorder associated with PCIP protein,nucleic acid expression or activity. For example, mutations in a PCIPgene can be assayed in a biological sample. Such assays can be used forprognostic or predictive purpose to thereby phophylactically treat anindividual prior to the onset of a disorder characterized by orassociated with PCIP protein, nucleic acid expression or activity.

[0114] Another aspect of the invention pertains to monitoring theinfluence of agents (e.g., drugs, compounds) on the expression oractivity of PCIP in clinical trials.

[0115] These and other agents are described in further detail in thefollowing sections.

[0116] 1. Diagnostic Assays

[0117] An exemplary method for detecting the presence or absence of PCIPprotein or nucleic acid in a biological sample involves obtaining abiological sample from a test subject and contacting the biologicalsample with a compound or an agent capable of detecting PCIP protein ornucleic acid (e.g., mRNA, genomic DNA) that encodes PCIP protein suchthat the presence of PCIP protein or nucleic acid is detected in thebiological sample. A preferred agent for detecting PCIP mRNA or genomicDNA is a labeled nucleic acid probe capable of hybridizing to PCIP mRNAor genomic DNA. The nucleic acid probe can be, for example, afull-length PCIP nucleic acid, such as the nucleic acid of SEQ ID NO:1,SEQ ID NO:3 SEQ ID NO:5, SEQ ID NO:7, SEQ ID NO:9, SEQ ID NO:11, SEQ IDNO:13, SEQ ID NO:15, SEQ ID NO:17, SEQ ID NO:19, SEQ ID NO:21, SEQ IDNO:23, SEQ ID NO:25, SEQ ID NO:27, SEQ ID NO:29, SEQ ID NO:31, SEQ IDNO:33, SEQ ID NO:35, SEQ ID NO:37, SEQ ID NO:39, SEQ ID NO:46, SEQ IDNO:47, SEQ ID NO:48, SEQ ID NO:50, SEQ ID NO:52, SEQ ID NO:54, SEQ IDNO:56, SEQ ID NO:58, SEQ ID NO:69, or SEQ ID NO:71, or the DNA insert ofthe plasmid deposited with ATCC as Accession Number 98936, 98937, 98938,98939, 98940, 98941, 98942, 98943, 98944, 98945, 98946, 98947, 98948,98949, 98950, 98951, 98991, 98993, or 98994, or a portion thereof, suchas an oligonucleotide of at least 15, 30, 50, 100, 250 or 500nucleotides in length and sufficient to specifically hybridize understringent conditions to PCIP mRNA or genomic DNA. Other suitable probesfor use in the diagnostic assays of the invention are described herein.

[0118] A preferred agent for detecting PCIP protein is an antibodycapable of binding to PCIP protein, preferably an antibody with adetectable label. Antibodies can be polyclonal, or more preferably,monoclonal. An intact antibody, or a fragment thereof (e.g., Fab orF(ab′)₂) can be used. The term “labeled”, with regard to the probe orantibody, is intended to encompass direct labeling of the probe orantibody by coupling (i.e., physically linking) a detectable substanceto the probe or antibody, as well as indirect labeling of the probe orantibody by reactivity with another reagent that is directly labeled.Examples of indirect labeling include detection of a primary antibodyusing a fluorescently labeled secondary antibody and end-labeling of aDNA probe with biotin such that it can be detected with fluorescentlylabeled streptavidin. The term “biological sample” is intended toinclude tissues, cells and biological fluids isolated from a subject, aswell as tissues, cells and fluids present within a subject. That is, thedetection method of the invention can be used to detect PCIP mRNA,protein, or genomic DNA in a biological sample in vitro as well as invivo. For example, in vitro techniques for detection of PCIP mRNAinclude Northern hybridizations and in situ hybridizations. In vitrotechniques for detection of PCIP protein include enzyme linkedimmunosorbent assays (ELISAs), Western blots, immunoprecipitations andimmunofluorescence. In vitro techniques for detection of PCIP genomicDNA include Southern hybridizations. Furthermore, in vivo techniques fordetection of PCIP protein include introducing into a subject a labeledanti-PCIP antibody. For example, the antibody can be labeled with aradioactive marker whose presence and location in a subject can bedetected by standard imaging techniques.

[0119] In one embodiment, the biological sample contains proteinmolecules from the test subject. Alternatively, the biological samplecan contain mRNA molecules from the test subject or genomic DNAmolecules from the test subject. A preferred biological sample is aserum sample isolated by conventional means from a subject.

[0120] In another embodiment, the methods further involve obtaining acontrol biological sample from a control subject, contacting the controlsample with a compound or agent capable of detecting PCIP protein, mRNA,or genomic DNA, such that the presence of PCIP protein, mRNA or genomicDNA is detected in the biological sample, and comparing the presence ofPCIP protein, mRNA or genomic DNA in the control sample with thepresence of PCIP protein, mRNA or genomic DNA in the test sample.

[0121] The invention also encompasses kits for detecting the presence ofPCIP in a biological sample. For example, the kit can comprise a labeledcompound or agent capable of detecting PCIP protein or mRNA in abiological sample; means for determining the amount of PCIP in thesample; and means for comparing the amount of PCIP in the sample with astandard. The compound or agent can be packaged in a suitable container.The kit can further comprise instructions for using the kit to detectPCIP protein or nucleic acid.

[0122] 2. Prognostic Assays

[0123] The diagnostic methods described herein can furthermore beutilized to identify subjects having or at risk of developing a diseaseor disorder associated with aberrant PCIP expression or activity. Forexample, the assays described herein, such as the preceding diagnosticassays or the following assays, can be utilized to identify a subjecthaving or at risk of developing a disorder associated with amisregulation in PCIP protein activity or nucleic acid expression, suchas a cardiovascular disorders such as sinus node disfunction, angina,heart failure, hypertension, atrial fibrillation, atrial flutter,dilated cardiomyopathy, idiopathic cardiomyopathy, myocardialinfarction, coronary artery disease, coronary artery spasm, orarrythmia.

[0124] Alternatively, the prognostic assays can be utilized to identifya subject having or at risk for developing a disorder associated with amisregulation in PCIP protein activity or nucleic acid expression, suchas a potassium channel associated disorder. Thus, the present inventionprovides a method for identifying a disease or disorder associated withaberrant PCIP expression or activity in which a test sample is obtainedfrom a subject and PCIP protein or nucleic acid (e.g., mRNA or genomicDNA) is detected, wherein the presence of PCIP protein or nucleic acidis diagnostic for a subject having or at risk of developing a disease ordisorder associated with aberrant PCIP expression or activity. As usedherein, a “test sample” refers to a biological sample obtained from asubject of interest. For example, a test sample can be a biologicalfluid (e.g., serum), cell sample, or tissue.

[0125] Furthermore, the prognostic assays described herein can be usedto determine whether a subject can be administered an agent (e.g., anagonist, antagonist, peptidomimetic, protein, peptide, nucleic acid,small molecule, or other drug candidate) to treat a disease or disorderassociated with aberrant PCIP expression or activity. For example, suchmethods can be used to determine whether a subject can be effectivelytreated with an agent for a cardiovascular disorder. Thus, the presentinvention provides methods for determining whether a subject can beeffectively treated with an agent for a disorder associated withaberrant PCIP expression or activity in which a test sample is obtainedand PCIP protein or nucleic acid expression or activity is detected(e.g., wherein the abundance of PCIP protein or nucleic acid expressionor activity is diagnostic for a subject that can be administered theagent to treat a disorder associated with aberrant PCIP expression oractivity).

[0126] The methods of the invention can also be used to detect geneticalterations in a PCIP gene, thereby determining if a subject with thealtered gene is at risk for a disorder characterized by misregulation inPCIP protein activity or nucleic acid expression, such as acardiovascular disorder. In preferred embodiments, the methods includedetecting, in a sample of cells from the subject, the presence orabsence of a genetic alteration characterized by at least one of analteration affecting the integrity of a gene encoding a PCIP-protein, orthe mis-expression of the PCIP gene. For example, such geneticalterations can be detected by ascertaining the existence of at leastone of 1) a deletion of one or more nucleotides from a PCIP gene; 2) anaddition of one or more nucleotides to a PCIP gene; 3) a substitution ofone or more nucleotides of a PCIP gene, 4) a chromosomal rearrangementof a PCIP gene; 5) an alteration in the level of a messenger RNAtranscript of a PCIP gene, 6) aberrant modification of a PCIP gene, suchas of the methylation pattern of the genomic DNA, 7) the presence of anon-wild type splicing pattern of a messenger RNA transcript of a PCIPgene, 8) a non-wild type level of a PCIP-protein, 9) allelic loss of aPCIP gene, and 10) inappropriate post-translational modification of aPCIP-protein. As described herein, there are a large number of assaysknown in the art which can be used for detecting alterations in a PCIPgene. A preferred biological sample is a tissue or serum sample isolatedby conventional means from a subject.

[0127] In certain embodiments, detection of the alteration involves theuse of a probe/primer in a polymerase chain reaction (PCR) (see, e.g.,U.S. Pat. Nos. 4,683,195 and 4,683,202), such as anchor PCR or RACE PCR,or, alternatively, in a ligation chain reaction (LCR) (see, e.g.,Landegran et al. (1988) Science 241:1077-1080; and Nakazawa et al.(1994) Proc. Natl. Acad. Sci. USA 91:360-364), the latter of which canbe particularly useful for detecting point mutations in the PCIP-gene(see Abravaya et al. (1995) Nucleic Acids Res .23:675-682). This methodcan include the steps of collecting a sample of cells from a subject,isolating nucleic acid (e.g., genomic, mRNA or both) from the cells ofthe sample, contacting the nucleic acid sample with one or more primerswhich specifically hybridize to a PCIP gene under conditions such thathybridization and amplification of the PCIP-gene (if present) occurs,and detecting the presence or absence of an amplification product, ordetecting the size of the amplification product and comparing the lengthto a control sample. It is anticipated that PCR and/or LCR may bedesirable to use as a preliminary amplification step in conjunction withany of the techniques used for detecting mutations described herein.

[0128] Alternative amplification methods include: self sustainedsequence replication (Guatelli, J. C. et al., (1990) Proc. Natl. Acad.Sci. USA 87:1874-1878), transcriptional amplification system (Kwoh, D.Y. et al., (1989) Proc. Natl. Acad. Sci. USA 86:1173-1177), Q-BetaReplicase (Lizardi, P. M. et al. (1988) Bio-Technology 6:1197), or anyother nucleic acid amplification method, followed by the detection ofthe amplified molecules using techniques well known to those of skill inthe art. These detection schemes are especially useful for the detectionof nucleic acid molecules if such molecules are present in very lownumbers.

[0129] In an alternative embodiment, mutations in a PCIP gene from asample cell can be identified by alterations in restriction enzymecleavage patterns. For example, sample and control DNA is isolated,amplified (optionally), digested with one or more restrictionendonucleases, and fragment length sizes are determined by gelelectrophoresis and compared. Differences in fragment length sizesbetween sample and control DNA indicates mutations in the sample DNA.Moreover, the use of sequence specific ribozymes (see, for example, U.S.Pat. No. 5,498,531) can be used to score for the presence of specificmutations by development or loss of a ribozyme cleavage site.

[0130] In other embodiments, genetic mutations in PCIP can be identifiedby hybridizing a sample and control nucleic acids, e.g., DNA or RNA, tohigh density arrays containing hundreds or thousands of oligonucleotidesprobes (Cronin, M. T. et al. (1996) Human Mutation 7: 244-255; Kozal, M.J. et al. (1996) Nature Medicine 2: 753-759). For example, geneticmutations in PCIP can be identified in two dimensional arrays containinglight-generated DNA probes as described in Cronin, M. T. et al. supraBriefly, a first hybridization array of probes can be used to scanthrough long stretches of DNA in a sample and control to identify basechanges between the sequences by making linear arrays of sequentialoverlapping probes. This step allows the identification of pointmutations. This step is followed by a second hybridization array thatallows the characterization of specific mutations by using smaller,specialized probe arrays complementary to all variants or mutationsdetected. Each mutation array is composed of parallel probe sets, onecomplementary to the wild-type gene and the other complementary to themutant gene.

[0131] In yet another embodiment, any of a variety of sequencingreactions known in the art can be used to directly sequence the PCIPgene and detect mutations by comparing the sequence of the sample PCIPwith the corresponding wild-type (control) sequence. Examples ofsequencing reactions include those based on techniques developed byMaxam and Gilbert ((1977) Proc. Natl. Acad. Sci. USA 74:560) or Sanger((1977) Proc. Natl. Acad. Sci. USA 74:5463). It is also contemplatedthat any of a variety of automated sequencing procedures can be utilizedwhen performing the diagnostic assays ((1995) Biotechniques 19:448),including sequencing by mass spectrometry (see, e.g., PCT InternationalPublication No. WO 94/16101; Cohen et al. (1996) Adv. Chromatogr.36:127-162; and Griffin et al. (1993) Appl. Biochem. Biotechnol.38:147-159).

[0132] Other methods for detecting mutations in the PCIP gene includemethods in which protection from cleavage agents is used to detectmismatched bases in RNA/RNA or RNA/DNA heteroduplexes (Myers et al.(1985) Science 230:1242). In general, the art technique of “mismatchcleavage” starts by providing heteroduplexes of formed by hybridizing(labeled) RNA or DNA containing the wild-type PCIP sequence withpotentially mutant RNA or DNA obtained from a tissue sample. Thedouble-stranded duplexes are treated with an agent which cleavessingle-stranded regions of the duplex such as which will exist due tobasepair mismatches between the control and sample strands. Forinstance, RNA/DNA duplexes can be treated with RNase and DNA/DNA hybridstreated with S1 nuclease to enzymatically digesting the mismatchedregions. In other embodiments, either DNA/DNA or RNA/DNA duplexes can betreated with hydroxylamine or osmium tetroxide and with piperidine inorder to digest mismatched regions. After digestion of the mismatchedregions, the resulting material is then separated by size on denaturingpolyacrylamide gels to determine the site of mutation. See, for example,Cotton et al. (1988) Proc. Natl Acad Sci USA 85:4397; Saleebaet al.(1992) Methods Enzymol. 217:286-295. In a preferred embodiment, thecontrol DNA or RNA can be labeled for detection.

[0133] In still another embodiment, the mismatch cleavage reactionemploys one or more proteins that recognize mismatched base pairs indouble-stranded DNA (so called “DNA mismatch repair” enzymes) in definedsystems for detecting and mapping point mutations in PCIP cDNAs obtainedfrom samples of cells. For example, the mutY enzyme of E. coli cleaves Aat G/A mismatches and the thymidine DNA glycosylase from HeLa cellscleaves T at G/T mismatches (Hsu et al. (1994) Carcinogenesis15:1657-1662). According to an exemplary embodiment, a probe based on aPCIP sequence, e.g., a wild-type PCIP sequence, is hybridized to a cDNAor other DNA product from a test cell(s). The duplex is treated with aDNA mismatch repair enzyme, and the cleavage products, if any, can bedetected from electrophoresis protocols or the like. See, for example,U.S. Pat. No. 5,459,039.

[0134] In other embodiments, alterations in electrophoretic mobilitywill be used to identify mutations in PCIP genes. For example, singlestrand conformation polymorphism (SSCP) may be used to detectdifferences in electrophoretic mobility between mutant and wild typenucleic acids (Orita et al. (1989) Proc Natl. Acad. Sci USA: 86:2766,see also Cotton (1993) Mutat. Res. 285:125-144; and Hayashi (1992)Genet. Anal. Tech. Appl. 9:73-79). Single-stranded DNA fragments ofsample and control PCIP nucleic acids will be denatured and allowed torenature. The secondary structure of single-stranded nucleic acidsvaries according to sequence, the resulting alteration inelectrophoretic mobility enables the detection of even a single basechange. The DNA fragments may be labeled or detected with labeledprobes. The sensitivity of the assay may be enhanced by using RNA(rather than DNA), in which the secondary structure is more sensitive toa change in sequence. In a preferred embodiment, the subject methodutilizes heteroduplex analysis to separate double stranded heteroduplexmolecules on the basis of changes in electrophoretic mobility (Keen etal. (1991) Trends Genet 7:5).

[0135] In yet another embodiment the movement of mutant or wild-typefragments in polyacrylamide gels containing a gradient of denaturant isassayed using denaturing gradient gel electrophoresis (DGGE) (Myers etal. (1985) Nature 313:495). When DGGE is used as the method of analysis,DNA will be modified to insure that it does not completely denature, forexample by adding a GC clamp of approximately 40 bp of high-meltingGC-rich DNA by PCR. In a further embodiment, a temperature gradient isused in place of a denaturing gradient to identify differences in themobility of control and sample DNA (Rosenbaum and Reissner (1987)Biophys Chem 265:12753).

[0136] Examples of other techniques for detecting point mutationsinclude, but are not limited to, selective oligonucleotidehybridization, selective amplification, or selective primer extension.For example, oligonucleotide primers may be prepared in which the knownmutation is placed centrally and then hybridized to target DNA underconditions which permit hybridization only if a perfect match is found(Saiki et al. (1986) Nature 324:163); Saiki et al. (1989) Proc. NatlAcad. Sci USA 86:6230). Such allele specific oligonucleotides arehybridized to PCR amplified target DNA or a number of differentmutations when the oligonucleotides are attached to the hybridizingmembrane and hybridized with labeled target DNA.

[0137] Alternatively, allele specific amplification technology whichdepends on selective PCR amplification may be used in conjunction withthe instant invention. Oligonucleotides used as primers for specificamplification may carry the mutation of interest in the center of themolecule (so that amplification depends on differential hybridization)(Gibbs et al. (1989) Nucleic Acids Res. 17:2437-2448) or at the extreme3′ end of one primer where, under appropriate conditions, mismatch canprevent, or reduce polymerase extension (Prossner (1993) Tibtech11:238). In addition it may be desirable to introduce a novelrestriction site in the region of the mutation to create cleavage-baseddetection (Gasparini et al. (1992) Mol. Cell Probes 6:1). It isanticipated that in certain embodiments amplification may also beperformed using Taq ligase for amplification (Barany (1991) Proc. Natl.Acad. Sci USA 88:189). In such cases, ligation will occur only if thereis a perfect match at the 3′ end of the 5′ sequence making it possibleto detect the presence of a known mutation at a specific site by lookingfor the presence or absence of amplification.

[0138] The methods described herein may be performed, for example, byutilizing pre-packaged diagnostic kits comprising at least one probenucleic acid or antibody reagent described herein, which may beconveniently used, e.g., in clinical settings to diagnose patientsexhibiting symptoms or family history of a disease or illness involvinga PCIP gene.

[0139] Furthermore, any cell type or tissue in which PCIP is expressedmay be utilized in the prognostic assays described herein.

[0140] 3. Monitoring of Effects during Clinical Trials

[0141] Monitoring the influence of agents (e.g., drugs) on theexpression or activity of a PCIP protein (e.g., the modulation ofmembrane excitability or resting potential) can be applied not only inbasic drug screening, but also in clinical trials. For example, theeffectiveness of an agent determined by a screening assay as describedherein to increase PCIP gene expression, protein levels, or upregulatePCIP activity, can be monitored in clinical trials of subjectsexhibiting decreased PCIP gene expression, protein levels, ordownregulated PCIP activity. Alternatively, the effectiveness of anagent determined by a screening assay to decrease PCIP gene expression,protein levels, or downregulate PCIP activity, can be monitored inclinical trials of subjects exhibiting increased PCIP gene expression,protein levels, or upregulated PCIP activity. In such clinical trials,the expression or activity of a PCIP gene, and preferably, other genesthat have been implicated in, for example, a potassium channelassociated disorder can be used as a “read out” or markers of thephenotype of a particular cell.

[0142] For example, and not by way of limitation, genes, including PCIP,that are modulated in cells by treatment with an agent (e.g., compound,drug or small molecule) which modulates PCIP activity (e.g., identifiedin a screening assay as described herein) can be identified. Thus, tostudy the effect of agents on potassium channel associated disorders,for example, in a clinical trial, cells can be isolated and RNA preparedand analyzed for the levels of expression of PCIP and other genesimplicated in the potassium channel associated disorder, respectively.The levels of gene expression (e.g., a gene expression pattern) can bequantified by northern blot analysis or RT-PCR, as described herein, oralternatively by measuring the amount of protein produced, by one of themethods as described herein, or by measuring the levels of activity ofPCIP or other genes. In this way, the gene expression pattern can serveas a marker, indicative of the physiological response of the cells tothe agent. Accordingly, this response state may be determined before,and at various points during treatment of the individual with the agent.

[0143] In a preferred embodiment, the present invention provides amethod for monitoring the effectiveness of treatment of a subject withan agent (e.g., an agonist, antagonist, peptidomimetic, protein,peptide, nucleic acid, small molecule, or other drug candidateidentified by the screening assays described herein) including the stepsof (i) obtaining a pre-administration sample from a subject prior toadministration of the agent; (ii) detecting the level of expression of aPCIP protein, mRNA, or genomic DNA in the preadministration sample;(iii) obtaining one or more post-administration samples from thesubject; (iv) detecting the level of expression or activity of the PCIPprotein, mRNA, or genomic DNA in the post-administration samples; (v)comparing the level of expression or activity of the PCIP protein, mRNA,or genomic DNA in the pre-administration sample with the PCIP protein,mRNA, or genomic DNA in the post administration sample or samples; and(vi) altering the administration of the agent to the subjectaccordingly. For example, increased administration of the agent may bedesirable to increase the expression or activity of PCIP to higherlevels than detected, i.e., to increase the effectiveness of the agent.Alternatively, decreased administration of the agent may be desirable todecrease expression or activity of PCIP to lower levels than detected,i.e. to decrease the effectiveness of the agent. According to such anembodiment, PCIP expression or activity may be used as an indicator ofthe effectiveness of an agent, even in the absence of an observablephenotypic response.

[0144] III. Methods of Treatment:

[0145] The present invention provides for both prophylactic andtherapeutic methods of treating a subject at risk of (or susceptible to)a disorder or having a disorder associated with aberrant PCIP expressionor activity such as a cardiovascular disorder. With regard to bothprophylactic and therapeutic methods of treatment, such treatments maybe specifically tailored or modified, based on knowledge obtained fromthe field of pharmacogenomics. “Pharmacogenomics”, as used herein,refers to the application of genomics technologies such as genesequencing, statistical genetics, and gene expression analysis to drugsin clinical development and on the market. More specifically, the termrefers the study of how a patient's genes determine his or her responseto a drug (e.g., a patient's “drug response phenotype”, or “drugresponse genotype”.) Thus, another aspect of the invention providesmethods for tailoring an individual's prophylactic or therapeutictreatment with either the PCIP molecules of the present invention orPCIP modulators according to that individual's drug response genotype.Pharmacogenomics allows a clinician or physician to target prophylacticor therapeutic treatments to patients who will most benefit from thetreatment and to avoid treatment of patients who will experience toxicdrug-related side effects.

[0146] 1. Prophylactic Methods

[0147] In one aspect, the invention provides a method for preventing ina subject, a disease or condition associated with an aberrant PCIPexpression or activity such as a cardiovascular disorder, byadministering to the subject a PCIP or an agent which modulates PCIPexpression or at least one PCIP activity. Subjects at risk for a diseasewhich is caused or contributed to by aberrant PCIP expression oractivity can be identified by, for example, any or a combination ofdiagnostic or prognostic assays as described herein. Administration of aprophylactic agent can occur prior to the manifestation of symptomscharacteristic of the PCIP aberrancy, such that a disease or disorder isprevented or, alternatively, delayed in its progression. Depending onthe type of PCIP aberrancy, for example, a PCIP, PCIP agonist or PCIPantagonist agent can be used for treating the subject. The appropriateagent can be determined based on screening assays described herein.

[0148] 2. Therapeutic Methods

[0149] Another aspect of the invention pertains to methods of modulatingPCIP expression or activity for therapeutic purposes. Accordingly, in anexemplary embodiment, the modulatory method of the invention involvescontacting a cell with a PCIP or agent that modulates one or more of theactivities of PCIP protein activity associated with the cell. An agentthat modulates PCIP protein activity can be an agent as describedherein, such as a nucleic acid or a protein, a naturally-occurringtarget molecule of a PCIP protein (e.g., a PCIP substrate), a PCIPantibody, a PCIP agonist or antagonist, a peptidomimetic of a PCIPagonist or antagonist, or other small molecule. In one embodiment, theagent stimulates one or more PCIP activities. Examples of suchstimulatory agents include active PCIP protein and a nucleic acidmolecule encoding PCIP that has been introduced into the cell. Inanother embodiment, the agent inhibits one or more PCIP activities.Examples of such inhibitory agents include antisense PCIP nucleic acidmolecules, anti-PCIP antibodies, and PCIP inhibitors. These modulatorymethods can be performed in vitro (e.g., by culturing the cell with theagent) or, alternatively, in vivo (e.g., by administering the agent to asubject). As such, the present invention provides methods of treating anindividual afflicted with a disease or disorder characterized byaberrant expression or activity of a PCIP protein or nucleic acidmolecule. Examples of such disorders include cardiovascular disorderssuch as long-QT syndrome, sinus node disfunction, angina, heart failure,hypertension, atrial fibrillation, atrial flutter, dilatedcardiomyopathy, idiopathic cardiomyopathy, myocardial infarction,coronary artery disease, coronary artery spasm, or arrythmia. In oneembodiment, the method involves administering an agent (e.g., an agentidentified by a screening assay described herein), or combination ofagents that modulates (e.g., upregulates or downregulates) PCIPexpression or activity. In another embodiment, the method involvesadministering a PCIP protein or nucleic acid molecule as therapy tocompensate for reduced or aberrant PCIP expression or activity.

[0150] Stimulation of PCIP activity is desirable in situations in whichPCIP is abnormally downregulated and/or in which increased PCIP activityis likely to have a beneficial effect. For example, stimulation of PCIPactivity is desirable in situations in which a PCIP is downregulatedand/or in which increased PCIP activity is likely to have a beneficialeffect. Likewise, inhibition of PCIP activity is desirable in situationsin which PCIP is abnormally upregulated and/or in which decreased PCIPactivity is likely to have a beneficial effect.

[0151] A PCIP molecule or an agent that modulates one or more of theactivities of PCIP protein activity associated with the cell can beincorporated into pharmaceutical compositions suitable foradministration. Such compositions typically comprise the nucleic acidmolecule, protein, or antibody and a pharmaceutically acceptablecarrier. As used herein the language “pharmaceutically acceptablecarrier” is intended to include any and all solvents, dispersion media,coatings, antibacterial and antifungal agents, isotonic and absorptiondelaying agents, and the like, compatible with pharmaceuticaladministration. The use of such media and agents for pharmaceuticallyactive substances is well known in the art. Except insofar as anyconventional media or agent is incompatible with the active compound,use thereof in the compositions is contemplated. Supplementary activecompounds can also be incorporated into the compositions.

[0152] A pharmaceutical composition used in the methods of the inventionis formulated to be compatible with its intended route ofadministration. Examples of routes of administration include parenteral,e.g., intravenous, intradermal, subcutaneous, oral (e.g., inhalation),transdermal (topical), transmucosal, and rectal administration.Solutions or suspensions used for parenteral, intradermal, orsubcutaneous application can include the following components: a sterilediluent such as water for injection, saline solution, fixed oils,polyethylene glycols, glycerine, propylene glycol or other syntheticsolvents; antibacterial agents such as benzyl alcohol or methylparabens; antioxidants such as ascorbic acid or sodium bisulfite;chelating agents such as ethylenediaminetetraacetic acid; buffers suchas acetates, citrates or phosphates and agents for the adjustment oftonicity such as sodium chloride or dextrose. pH can be adjusted withacids or bases, such as hydrochloric acid or sodium hydroxide. Theparenteral preparation can be enclosed in ampoules, disposable syringesor multiple dose vials made of glass or plastic.

[0153] Pharmaceutical compositions suitable for injectable use includesterile aqueous solutions (where water soluble) or dispersions andsterile powders for the extemporaneous preparation of sterile injectablesolutions or dispersion. For intravenous administration, suitablecarriers include physiological saline, bacteriostatic water, CremophorEL™ (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS). In allcases, the composition must be sterile and should be fluid to the extentthat easy syringability exists. It must be stable under the conditionsof manufacture and storage and must be preserved against thecontaminating action of microorganisms such as bacteria and fungi. Thecarrier can be a solvent or dispersion medium containing, for example,water, ethanol, polyol (for example, glycerol, propylene glycol, andliquid polyetheylene glycol, and the like), and suitable mixturesthereof. The proper fluidity can be maintained, for example, by the useof a coating such as lecithin, by the maintenance of the requiredparticle size in the case of dispersion and by the use of surfactants.Prevention of the action of microorganisms can be achieved by variousantibacterial and antifungal agents, for example, parabens,chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In manycases, it will be preferable to include isotonic agents, for example,sugars, polyalcohols such as manitol, sorbitol, sodium chloride in thecomposition. Prolonged absorption of the injectable compositions can bebrought about by including in the composition an agent which delaysabsorption, for example, aluminum monostearate and gelatin.

[0154] Sterile injectable solutions can be prepared by incorporating theactive compound (e.g., a fragment of a PCIP protein or an anti-PCIPantibody) in the required amount in an appropriate solvent with one or acombination of ingredients enumerated above, as required, followed byfiltered sterilization. Generally, dispersions are prepared byincorporating the active compound into a sterile vehicle which containsa basic dispersion medium and the required other ingredients from thoseenumerated above. In the case of sterile powders for the preparation ofsterile injectable solutions, the preferred methods of preparation arevacuum drying and freeze-drying which yields a powder of the activeingredient plus any additional desired ingredient from a previouslysterile-filtered solution thereof.

[0155] Oral compositions generally include an inert diluent or an ediblecarrier. They can be enclosed in gelatin capsules or compressed intotablets. For the purpose of oral therapeutic administration, the activecompound can be incorporated with excipients and used in the form oftablets, troches, or capsules. Oral compositions can also be preparedusing a fluid carrier for use as a mouthwash, wherein the compound inthe fluid carrier is applied orally and swished and expectorated orswallowed. Pharmaceutically compatible binding agents, and/or adjuvantmaterials can be included as part of the composition. The tablets,pills, capsules, troches and the like can contain any of the followingingredients, or compounds of a similar nature: a binder such asmicrocrystalline cellulose, gum tragacanth or gelatin; an excipient suchas starch or lactose, a disintegrating agent such as alginic acid,Primogel, or corn starch; a lubricant such as magnesium stearate orSterotes; a glidant such as colloidal silicon dioxide; a sweeteningagent such as sucrose or saccharin; or a flavoring agent such aspeppermint, methyl salicylate, or orange flavoring.

[0156] For administration by inhalation, the compounds are delivered inthe form of an aerosol spray from pressured container or dispenser whichcontains a suitable propellant, e.g., a gas such as carbon dioxide, or anebulizer.

[0157] Systemic administration can also be by transmucosal ortransdermal means. For transmucosal or transdermal administration,penetrants appropriate to the barrier to be permeated are used in theformulation. Such penetrants are generally known in the art, andinclude, for example, for transmucosal administration, detergents, bilesalts, and fusidic acid derivatives. Transmucosal administration can beaccomplished through the use of nasal sprays or suppositories. Fortransdermal administration, the active compounds are formulated intoointments, salves, gels, or creams as generally known in the art.

[0158] The pharmaceutical compositions used in the methods of theinvention can also be prepared in the form of suppositories (e.g., withconventional suppository bases such as cocoa butter and otherglycerides) or retention enemas for rectal delivery.

[0159] In one embodiment, pharmaceutical compositions used in themethods of the invention are prepared with carriers that will protectthe active compound against rapid elimination from the body, such as acontrolled release formulation, including implants and microencapsulateddelivery systems. Biodegradable, biocompatible polymers can be used,such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid,collagen, polyorthoesters, and polylactic acid. Methods for preparationof such formulations will be apparent to those skilled in the art. Thematerials can also be obtained commercially from Alza Corporation andNova Pharmaceuticals, Inc. Liposomal suspensions (including liposomestargeted to infected cells with monoclonal antibodies to viral antigens)can also be used as pharmaceutically acceptable carriers. These can beprepared according to methods known to those skilled in the art, forexample, as described in U.S. Pat. No. 4,522,811.

[0160] It is especially advantageous to formulate oral or parenteralcompositions in dosage unit form for ease of administration anduniformity of dosage. Dosage unit form as used herein refers tophysically discrete units suited as unitary dosages for the subject tobe treated; each unit containing a predetermined quantity of activecompound calculated to produce the desired therapeutic effect inassociation with the required pharmaceutical carrier. The specificationfor the dosage unit forms of the invention are dictated by and directlydependent on the unique characteristics of the active compound and theparticular therapeutic effect to be achieved, and the limitationsinherent in the art of compounding such an active compound for thetreatment of individuals.

[0161] Toxicity and therapeutic efficacy of such compounds can bedetermined by standard pharmaceutical procedures in cell cultures orexperimental animals, e.g., for determining the LD50 (the dose lethal to50% of the population) and the ED50 (the dose therapeutically effectivein 50% of the population). The dose ratio between toxic and therapeuticeffects is the therapeutic index and it can be expressed as the ratioLD50/ED50. Compounds which exhibit large therapeutic indices arepreferred. While compounds that exhibit toxic side effects may be used,care should be taken to design a delivery system that targets suchcompounds to the site of affected tissue in order to minimize potentialdamage to uninfected cells and, thereby, reduce side effects.

[0162] The data obtained from the cell culture assays and animal studiescan be used in formulating a range of dosage for use in humans. Thedosage of such compounds lies preferably within a range of circulatingconcentrations that include the ED50 with little or no toxicity. Thedosage may vary within this range depending upon the dosage formemployed and the route of administration utilized. For any compound usedin the method of the invention, the therapeutically effective dose canbe estimated initially from cell culture assays. A dose may beformulated in animal models to achieve a circulating plasmaconcentration range that includes the IC50 (i.e., the concentration ofthe test compound which achieves a half-maximal inhibition of symptoms)as determined in cell culture. Such information can be used to moreaccurately determine useful doses in humans. Levels in plasma may bemeasured, for example, by high performance liquid chromatography.

[0163] As defined herein, a therapeutically effective amount of proteinor polypeptide (i.e., an effective dosage) ranges from about 0.001 to 30mg/kg body weight, preferably about 0.01 to 25 mg/kg body weight, morepreferably about 0.1 to 20 mg/kg body weight, and even more preferablyabout 1 to 10 mg/kg, 2 to 9 mg/kg, 3 to 8 mg/kg, 4 to 7 mg/kg, or 5 to 6mg/kg body weight. The skilled artisan will appreciate that certainfactors may influence the dosage required to effectively treat asubject, including but not limited to the severity of the disease ordisorder, previous treatments, the general health and/or age of thesubject, and other diseases present. Moreover, treatment of a subjectwith a therapeutically effective amount of a protein, polypeptide, orantibody can include a single treatment or, preferably, can include aseries of treatments.

[0164] In a preferred example, a subject is treated with antibody,protein, or polypeptide in the range of between about 0.1 to 20 mg/kgbody weight, one time per week for between about 1 to 10 weeks,preferably between 2 to 8 weeks, more preferably between about 3 to 7weeks, and even more preferably for about 4, 5, or 6 weeks. It will alsobe appreciated that the effective dosage of antibody, protein, orpolypeptide used for treatment may increase or decrease over the courseof a particular treatment. Changes in dosage may result and becomeapparent from the results of diagnostic assays as described herein.

[0165] The methods of the present invention encompasses the use ofagents which modulate expression or activity. An agent may, for example,be a small molecule. For example, such small molecules include, but arenot limited to, peptides, peptidomimetics, amino acids, amino acidanalogs, polynucleotides, polynucleotide analogs, nucleotides,nucleotide analogs, organic or inorganic compounds (i.e., includingheteroorganic and organometallic compounds) having a molecular weightless than about 10,000 grams per mole, organic or inorganic compoundshaving a molecular weight less than about 5,000 grams per mole, organicor inorganic compounds having a molecular weight less than about 1,000grams per mole, organic or inorganic compounds having a molecular weightless than about 500 grams per mole, and salts, esters, and otherpharmaceutically acceptable forms of such compounds. It is understoodthat appropriate doses of small molecule agents depends upon a number offactors within the ken of the ordinarily skilled physician,veterinarian, or researcher. The dose(s) of the small molecule willvary, for example, depending upon the identity, size, and condition ofthe subject or sample being treated, further depending upon the route bywhich the composition is to be administered, if applicable, and theeffect which the practitioner desires the small molecule to have uponthe nucleic acid or polypeptide of the invention. Exemplary dosesinclude milligram or microgram amounts of the small molecule perkilogram of subject or sample weight (e.g., about 1 microgram perkilogram to about 500 milligrams per kilogram, about 100 micrograms perkilogram to about 5 milligrams per kilogram, or about 1 microgram perkilogram to about 50 micrograms per kilogram. It is furthermoreunderstood that appropriate doses of a small molecule depend upon thepotency of the small molecule with respect to the expression or activityto be modulated. Such appropriate doses may be determined using theassays described herein. When one or more of these small molecules is tobe administered to an animal (e.g., a human) in order to modulateexpression or activity of a polypeptide or nucleic acid of theinvention, a physician, veterinarian, or researcher may, for example,prescribe a relatively low dose at first, subsequently increasing thedose until an appropriate response is obtained. In addition, it isunderstood that the specific dose level for any particular animalsubject will depend upon a variety of factors including the activity ofthe specific compound employed, the age, body weight, general health,gender, and diet of the subject, the time of administration, the routeof administration, the rate of excretion, any drug combination, and thedegree of expression or activity to be modulated.

[0166] Further, an antibody (or fragment thereof) may be conjugated to atherapeutic moiety such as a cytotoxin, a therapeutic agent or aradioactive metal ion. A cytotoxin or cytotoxic agent includes any agentthat is detrimental to cells. Examples include taxol, cytochalasin B,gramicidin D, ethidium bromide, emetine, mitomycin, etoposide,tenoposide, vincristine, vinblastine, colchicin, doxorubicin,daunorubicin, dihydroxy anthracin dione, mitoxantrone, mithramycin,actinomycin D, 1-dehydrotestosterone, glucocorticoids, procaine,tetracaine, lidocaine, propranolol, and puromycin and analogs orhomologs thereof. Therapeutic agents include, but are not limited to,antimetabolites (e.g., methotrexate, 6-mercaptopurine, 6-thioguanine,cytarabine, 5-fluorouracil decarbazine), alkylating agents (e.g.,mechlorethamine, thioepa chlorambucil, melphalan, carmustine (BSNU) andlomustine (CCNU), cyclothosphamide, busulfan, dibromomannitol,streptozotocin, mitomycin C, and cis-dichlorodiamine platinum (II) (DDP)cisplatin), anthracyclines (e.g., daunorubicin (formerly daunomycin) anddoxorubicin), antibiotics (e.g., dactinomycin (formerly actinomycin),bleomycin, mithramycin, and anthramycin (AMC)), and anti-mitotic agents(e.g., vincristine and vinblastine).

[0167] The conjugates can be used for modifying a given biologicalresponse, the drug moiety is not to be construed as limited to classicalchemical therapeutic agents. For example, the drug moiety may be aprotein or polypeptide possessing a desired biological activity. Suchproteins may include, for example, a toxin such as abrin, ricin A,pseudomonas exotoxin, or diphtheria toxin; a protein such as tumornecrosis factor, alpha.-interferon, .beta.-interferon, nerve growthfactor, platelet derived growth factor, tissue plasminogen activator;or, biological response modifiers such as, for example, lymphokines,interleukin-1 (“IL-1”), interleukin-2 (“IL-2”), interleukin-6 (“IL-6”),granulocyte macrophase colony stimulating factor (“GM-CSF”), granulocytecolony stimulating factor (“G-CSF”), or other growth factors.

[0168] Techniques for conjugating such therapeutic moiety to antibodiesare well known, see, e.g., Arnon et al., “Monoclonal Antibodies ForImmunotargeting Of Drugs In Cancer Therapy”, in Monoclonal AntibodiesAnd Cancer Therapy, Reisfeld et al. (eds.), pp. 243-56 (Alan R. Liss,Inc. 1985); Hellstrom et al., “Antibodies For Drug Delivery”, inControlled Drug Delivery (2nd Ed.), Robinson et al. (eds.), pp. 623-53(Marcel Dekker, Inc. 1987); Thorpe, “Antibody Carriers Of CytotoxicAgents In Cancer Therapy: A Review”, in Monoclonal Antibodies '84:Biological And Clinical Applications, Pinchera et al. (eds.), pp.475-506 (1985); “Analysis, Results, And Future Prospective Of TheTherapeutic Use Of Radiolabeled Antibody In Cancer Therapy”, inMonoclonal Antibodies For Cancer Detection And Therapy, Baldwin et al.(eds.), pp. 303-16 (Academic Press 1985), and Thorpe et al., “ThePreparation And Cytotoxic Properties Of Antibody-Toxin Conjugates”,Immunol. Rev., 62:119-58 (1982). Alternatively, an antibody can beconjugated to a second antibody to Form an antibody heteroconjugate asdescribed by Segal in U.S. Pat. No. 4,676,980.

[0169] The nucleic acid molecules used in the methods of the inventioncan be inserted into vectors and used as gene therapy vectors. Genetherapy vectors can be delivered to a subject by, for example,intravenous injection, local administration (see U.S. Pat. No.5,328,470) or by stereotactic injection (see e.g., Chen et al. (1994)Proc. Natl. Acad. Sci. USA 91:3054-3057). The pharmaceutical preparationof the gene therapy vector can include the gene therapy vector in anacceptable diluent, or can comprise a slow release matrix in which thegene delivery vehicle is imbedded. Alternatively, where the completegene delivery vector can be produced intact from recombinant cells,e.g., retroviral vectors, the pharmaceutical preparation can include oneor more cells which produce the gene delivery system.

[0170] 3. Pharmacogenomics

[0171] The PCIP molecules of the present invention, as well as agents,or modulators which have a stimulatory or inhibitory effect on PCIPactivity (e.g., PCIP gene expression) as identified by a screening assaydescribed herein can be administered to individuals to treat(prophylactically or therapeutically) potassium channel associateddisorders associated with aberrant PCIP activity (e.g, cardiovasculardisorders such as long-QT syndrome, sinus node disfunction, angina,heart failure, hypertension, atrial fibrillation, atrial flutter,dilated cardiomyopathy, idiopathic cardiomyopathy, myocardialinfarction, coronary artery disease, coronary artery spasm, orarrythmia). In conjunction with such treatment, pharmacogenomics (i.e.,the study of the relationship between an individual's genotype and thatindividual's response to a foreign compound or drug) may be considered.Differences in metabolism of therapeutics can lead to severe toxicity ortherapeutic failure by altering the relation between dose and bloodconcentration of the pharmacologically active drug. Thus, a physician orclinician may consider applying knowledge obtained in relevantpharmacogenomics studies in determining whether to administer a PCIPmolecule or PCIP modulator as well as tailoring the dosage and/ortherapeutic regimen of treatment with a PCIP molecule or PCIP modulator.

[0172] Pharmacogenomics deals with clinically significant hereditaryvariations in the response to drugs due to altered drug disposition andabnormal action in affected persons. See, for example, Eichelbaum, M. etal. (1996) Clin. Exp. Pharmacol. Physiol. 23(10-11):983-985 and Linder,M. W. et al. (1997) Clin. Chem. 43(2):254-266. In general, two types ofpharmacogenetic conditions can be differentiated. Genetic conditionstransmitted as a single factor altering the way drugs act on the body(altered drug action) or genetic conditions transmitted as singlefactors altering the way the body acts on drugs (altered drugmetabolism). These pharmacogenetic conditions can occur either as raregenetic defects or as naturally-occurring polymorphisms. For example,glucose-6-phosphate dehydrogenase deficiency (G6PD) is a commoninherited enzymopathy in which the main clinical complication ishaemolysis after ingestion of oxidant drugs (anti-malarials,sulfonamides, analgesics, nitrofurans) and consumption of fava beans.

[0173] One pharmacogenomics approach to identifying genes that predictdrug response, known as “a genome-wide association”, relies primarily ona high-resolution map of the human genome consisting of already knowngene-related markers (e.g., a “bi-allelic” gene marker map whichconsists of 60,000-100,000 polymorphic or variable sites on the humangenome, each of which has two variants.) Such a high-resolution geneticmap can be compared to a map of the genome of each of a statisticallysignificant number of patients taking part in a Phase II/III drug trialto identify markers associated with a particular observed drug responseor side effect. Alternatively, such a high resolution map can begenerated from a combination of some ten-million known single nucleotidepolymorphisms (SNPs) in the human genome. As used herein, a “SNP” is acommon alteration that occurs in a single nucleotide base in a stretchof DNA. For example, a SNP may occur once per every 1000 bases of DNA. ASNP may be involved in a disease process, however, the vast majority maynot be disease-associated. Given a genetic map based on the occurrenceof such SNPs, individuals can be grouped into genetic categoriesdepending on a particular pattern of SNPs in their individual genome. Insuch a manner, treatment regimens can be tailored to groups ofgenetically similar individuals, taking into account traits that may becommon among such genetically similar individuals.

[0174] Alternatively, a method termed the “candidate gene approach”, canbe utilized to identify genes that predict drug response. According tothis method, if a gene that encodes a drugs target is known (e.g., aPCIP protein of the present invention), all common variants of that genecan be fairly easily identified in the population and it can bedetermined if having one version of the gene versus another isassociated with a particular drug response.

[0175] As an illustrative embodiment, the activity of drug metabolizingenzymes is a major determinant of both the intensity and duration ofdrug action. The discovery of genetic polymorphisms of drug metabolizingenzymes (e.g., N-acetyltransferase 2 (NAT 2) and cytochrome P450 enzymesCYP2D6 and CYP2C19) has provided an explanation as to why some patientsdo not obtain the expected drug effects or show exaggerated drugresponse and serious toxicity after taking the standard and safe dose ofa drug. These polymorphisms are expressed in two phenotypes in thepopulation, the extensive metabolizer (EM) and poor metabolizer (PM).The prevalence of PM is different among different populations. Forexample, the gene coding for CYP2D6 is highly polymorphic and severalmutations have been identified in PM, which all lead to the absence offunctional CYP2D6. Poor metabolizers of CYP2D6 and CYP2C19 quitefrequently experience exaggerated drug response and side effects whenthey receive standard doses. If a metabolite is the active therapeuticmoiety, PM show no therapeutic response, as demonstrated for theanalgesic effect of codeine mediated by its CYP2D6-formed metabolitemorphine. The other extreme are the so called ultra-rapid metabolizerswho do not respond to standard doses. Recently, the molecular basis ofultra-rapid metabolism has been identified to be due to CYP2D6 geneamplification.

[0176] Alternatively, a method termed the “gene expression profiling”,can be utilized to identify genes that predict drug response. Forexample, the gene expression of an animal dosed with a drug (e.g., aPCIP molecule or PCIP modulator of the present invention) can give anindication whether gene pathways related to toxicity have been turnedon.

[0177] Information generated from more than one of the abovepharmacogenomics approaches can be used to determine appropriate dosageand treatment regimens for prophylactic or therapeutic treatment anindividual. This knowledge, when applied to dosing or drug selection,can avoid adverse reactions or therapeutic failure and thus enhancetherapeutic or prophylactic efficiency when treating a subject with aPCIP molecule or PCIP modulator, such as a modulator identified by oneof the exemplary screening assays described herein.

[0178] This invention is further illustrated by the following exampleswhich should not be construed as limiting. The contents of allreferences, patents and published patent applications cited throughoutthis application, as well as the Figures and the Sequence Listing areincorporated herein by reference.

EXAMPLES

[0179] The following materials and methods were used in the Examples.

[0180] Strains, Plasmids, Bait cDNAs, and General MicrobiologicalTechniques

[0181] Basic yeast strains (HF7c, Y187,) bait (pGBT9) and fish (pACT2)plasmids used in this work were purchased from Clontech (Palo Alto,Calif.). cDNAs encoding rat Kv4.3, Kv4.2, and Kv1.1, were provided byWyeth-Ayerst Research (865 Ridge Rd., Monmouth Junction, N.J. 08852)Standard yeast media including synthetic complete medium lackingL-leucine, L-tryptophan, and L-histidine were prepared and yeast geneticmanipulations were performed as described (Sherman (1991) Meth. Enzymol.194:3-21). Yeast transformations were performed using standard protocols(Gietz et al. (1992) Nucleic Acids Res. 20:1425; Ito et al (1983) J.Bacteriol. 153:163-168). Plasmid DNAs were isolated from yeast strainsby a standard method (Hoffinan and Winston (1987) Gene 57:267-272).

[0182] Bait and Yeast Strain Construction

[0183] The first 180 amino acids of rKv4.3 (described in Serdio P. etal. (1996) J. Neurophys 75:2174-2179) were amplified by PCR and clonedin frame into pGBT9 resulting in plasmid pFWA2, (hereinafter “bait”).This bait was transformed into the two-hybrid screening strain HF7c andtested for expression and self-activation. The bait was validated forexpression by Western blotting. The rKv4.3 bait did not self-activate inthe presence of 10 mM 3-amino-1,2,3-Triazole (3-AT).

[0184] Library Construction

[0185] Rat mid brain tissue was provided by Wyeth-Ayerst Research(Monmouth Junction, N.J.). Total cellular RNA was extracted from thetissues using standard techniques (Sambrook, J., Fritsh, E. F., andManiatis, T. Molecular Cloning: A Laboratory Manual. 2nd, ed., ColdSpring Harbor Laboratory, Cold Spring Harbor Laboratory Press, ColdSpring Harbor, N.Y., (1989)). mRNA was prepared using a Poly-A Spin mRNAIsolation Kit from New England Biolabs (Beverly, Mass.). cDNA from themRNA sample was synthesized using a cDNA Synthesis Kit from Stratagene(La Jolla, Calif.) and ligated into pACT2's EcoRi and XhoI sites, givingrise to a two-hybrid library.

[0186] Two-hybrid Screening

[0187] Two-hybrid screens were carried out essentially as described inBartel, P. et al. (1993) “Using the Two-Hybrid System to DetectPolypeptide-Polypeptide Interactions” in Cellular Interactions inDevelopment: A Practical Approach, Hartley, D. A. ed. Oxford UniversityPress, Oxford, pp. 153-179, with a bait-library pair of rkv4.3 bait-ratmid brain library. A filter disk beta-galactosidase (beta-gal) assay wasperformed essentially as previously described (Brill et al. (1994) Mol.Biol. Cell. 5:297-312). Clones that were positive for both reporter geneactivity (His and beta-galactosidase) were scored and fish, plasmidswere isolated from yeast, transformed into E. coli strain KC8, DNAplasmids were purified and the resulting plasmids were sequenced byconventional methods (Sanger F. et al. (1977) PNAS, 74:5463-67).

[0188] Specificity Test

[0189] Positive interactor clones were subjected to a bindingspecificity test where they were exposed to a panel of related andunrelated baits by a mating scheme previously described (Finley R. L.Jr. et al. (1994) PNAS, 91(26):12980-12984). Briefly, positive fishplasmids were transformed into Y187 and the panel of baits weretransformed into HF7c. Transformed fish and bait cells were streaked outas stripes on selective medium plates, mated on YPAD plates, and testedfor reporter gene activity.

[0190] Analysis

[0191] PCIP nuleotides were analyzed for nucleic acid hits by the BLASTN1.4.8MP program (Altschul et al. (1990) Basic Local Alignment SearchTool. J. Mol. Biol. 215:403-410). PCIP proteins were analyzed forpolypeptide hits by the BLASTP 1.4.9MP program.

Example 1 Identification of Rat PCIP cDNAs

[0192] The Kv4.3 gene coding sequence (coding for the first 180 aminoacids) was amplified by PCR and cloned into pGBT9 creating a GAL4DNA-binding domain-Kv4.3(1-180) gene fusion (plasmid pFWA2). HF7c wastransformed with this construct. The resulting strain grew on syntheticcomplete medium lacking L-tryptophan but not on synthetic completemedium lacking L-tryptophan and L-histidine in the presence of 10 mM3-AT demonstrating that the {GAL4 DNA-binding domain}-{vKv4.3(1-180)}gene fusion does not have intrinsic transcriptional activation activityhigher than the threshhold allowed by 10 mM 3-AT.

[0193] In this example, a yeast two-hybrid assay was performed in whicha plasmid containing a {GAL4 DNA-binding domain}-{rKv4.3(1-180)} genefusion was introduced into the yeast two-hybrid screening strain HF7cdescribed above. HF7c was then transformed with the rat mid braintwo-hybrid library. Approximately six million transformants wereobtained and plated in selection medium. Colonies that grew in theselection medium and expressed the beta-galactosidase reporter gene werefurther characterized and subjected to retransformation and specificityassays. The retransformation and specificity tests yielded three PCIPclones (rat 1v, 8t, and 9qm) that were able to bind to the Kv4.3polypeptide.

[0194] The full length sequences for the rat 1v gene, and partialsequences for 8t and 9q genes were derived as follows. The partial ratPCIP sequences were used to prepare probes, which were then used toscreen, for example, rat mid brain cDNA libraries. Positive clones wereidentified, amplified and sequenced using standard techniques, to obtainthe full length sequence. Additionally, a rapid amplification of theexisting rat PCIP cDNA ends (using for example, 5′ RACE, by Gibco, BRL)was used to complete the 5′ end of the transcript.

Example 2 Identification of Human 1v cDNA

[0195] To obtain the human 1v nucleic acid molecule, a cDNA library madefrom a human hippocampus (Clontech, Palo Alto, Calif.) was screenedunder low stringency conditions as follows: Prehybridization for 4 hoursat 42° C. in Clontech Express Hyb solution, followed by overnighthybridization at 42° C. The probe used was a PCR-generated fragmentincluding nucletides 49-711 of the rat sequence labeled with 3²p dCTP.The filters were washed 6 times in 2× SSC/0.1% SDS at 55° C. The sameconditions were used for secondary screening of the positive isolates.Clones thus obtained were sequenced using an ABI automated DNASequencing system, and compared to the rat sequences shown in SEQ IDNO:3 as well as to known sequences from the GenBank database. Thelargest clone from the library screen was subsequently subcloned intopBS-KS+ (Stratagene, La Jolla, Calif.) for sequence verification. The515 base pair clone was determined to represent the human homolog of the1v gene, encompasing 211 base pairs of 5′ UTR and a 304 base pair codingregion. To generate the full-length cDNA, 3′ RACE was used according tothe manufacturers instructions (Clontech Advantage PCR kit).

Example 3 Isolation and Characterization of 1V Splice Variants

[0196] The mouse 1v shown in SEQ ID NO:5 and the rat 1vl splice variantshown in SEQ ID NO:7 was isolated using a two-hybrid assay as describedin Example 1. The mouse 1vl splice variant shown in SEQ ID NO:7 wasisolated by screening a mouse brain cDNA library, and the rat 1vn splicevariant shown in SEQ ID NO:11 was isolated by BLAST searching.

Example 4 Isolation and Identification of 9Q and Other PCIPs

[0197] Rat 9ql (SEQ ID NO:15) was isolated by database mining, rat 9qm(SEQ ID NO: 21) was isolated by a two-hybrid assay, and rat 9qc (SEQ IDNO:27) was identified by database mining. Human 9ql (SEQ ID NO: 13), andhuman 9qs (SEQ ID NO: 23) were identified as described in Example 2.Mouse 9ql (SEQ ID NO:17), monkey 9qs (SEQ ID NO:25), human p195 (SEQ IDNO:31), W28559 (SEQ ID NO:37), human p193 (SEQ ID NO:39), rat p19 (SEQID NO:33), and mouse p19 (SEQ ID NO:35) were identified by databasemining. Rat 8t (SEQ ID NO:29) was identified using a two-hybrid assay.

[0198] The human genomic 9q sequence (SEQ ID NOs:46 and 47) was isolatedby screening a BAC genomic DNA library (Reasearch Genetics) usingprimers which were designed based on the sequence of the human 9qm cDNA.Two positive clones were identified (44802 and 721117) and sequenced.

Example 5 Expression of p19, 1V, 8T, and 9Q mRNA in Rat Tissues

[0199] PCIP molecules, e.g., 9q and 8t, were demonstrated to bepredominantly expressed in the heart. Briefly, rator mouse multipletissue Northern blots (Clontech) were probed with a [³²P]-labeled cDNAprobe directed at the p19 sequence, the 5′-untranslated and 5′-codingregion of the rat 1v sequence (nucleotides 35-124; SEQ ID NO:3) (thisprobe is specific for rat 1v and rat 1vl), the 5′ coding region of the8t sequence (nucleotides 1-88; SEQ ID NO:29) (this probe is specific for8t), or the 5′ end of the rat 9qm sequence (nucleotides 1-195; SEQ IDNO:21) (this probe is specific for all 9q isoforms, besides 8t). Blotswere hybridized using standard techniques.

[0200] The results indicated that p19 is expressed predominantly in thebrain, but also in the heart. Moreover, northern blots hybridized withthe rat 1v probe revealed a single band at 2.3 kb only in the lanecontaining brain RNA, suggesting that 1v expression is brain specific.Northern blots probed with the rat 8t probe revealed a major band at 2.4kb. The rat 8t band was most intense in the lane containing heart RNAand there was also a weaker band in the lane containing brain RNA.Northern blots hybridized with the 9q cDNA probe revealed a major bandat 2.5 kb and a minor band at over 4 kb with predominant expression inheart and brain. The minor band may represent incompletely spliced orprocessed 9q mRNA.

Example 6 Expression of 1V, 8T, and 9Q in Brain

[0201] Expression of the rat 1v and 8t/9q genes in the brain wasexamined by in situ hybridization histochemistry (ISHH) using[³⁵S]-labeled cRNA probes and a hybridization procedure identical tothat described in Rhodes et al. (1996) J. Neurosci., 16:4846-4860.Templates for preparing the cRNA probes were generated by standard PCRmethods. Briefly, oligonucleotide primers were designed to amplify afragment of 3′- or 5′-untranslated region of the target cDNA and inaddition, add the promoter recognition sequences for T7 and T3polymerase. Thus, to generate a 300 nucleotide probe directed at the3′-untranslated region of the 1v mRNA, we used the following primers:

[0202] 5-TAATACGACTCACTATAGGGACTGGCCATCCTGCTCTCAG-3 (T7, forward, sense;SEQ ID NO:42)

[0203] 5-ATTAACCCTCACTAAAGGGACACTACTGTTTAAGCTCAAG-3 (T3, reverse,antisense; SEQ ID NO:43). The underlined bases correspond to the T7 andT3 promoter sequences. To generate a probe directed at a 325 bp regionof 3′-untranslated sequence shared by the 8t and 9q mRNAs, the followingprimers were used:

[0204] 5-TAATACGACTCACTATAGGGCACCTCCCCTCCGGCTGTTC-3 (T7, forward, sense;SEQ ID NO:44)

[0205] 5-ATTAACCCTCACTAAAGGGAGAGCAGCAGCATGGCAGGGT-3 (T3, reverse,antisense; SEQ ID NO:45).

[0206] Autoradiograms of rat brain tissue sections processed for ISHHlocalization of 1v or 8t/9q mRNA expression revealed that 1v mRNA isexpressed widely in brain in a pattern consistent with labeling ofneurons as opposed to glial or endothelial cells. 1v mRNA is highlyexpressed in cortical, hippocampal, and striatal interneurons, thereticlar nucleus of the thalamus, the medial habenula, and in cerebellargranule cells. 1v mRNA is expressed at moderate levels in midbrainnuclei including the substantia nigra and superior colliculus, inseveral other thalamic nuclei, and in the medial septal and diagonalband nuclei of the basal forebrain.

[0207] Because the probe used to analyze the expression of 8t and 9qhybridizes to a region of the 3-untranslated region that is identical inthe 8t and 9q mRNAs, this probe generates a composite image that revealsthat 8t/9q mRNA is expressed widely in brain in a pattern that partlyoverlaps with that for 1v as described above. However, 8t/9q mRNA ishighly expressed in the striatum, hippocampal formation, cerebellargranule cells, and neocortex. 8t/9q mRNA is expressed at moderate levelsin the midbrain, thalamus, and brainstem. In may of these areas, 8t./9qmRNA appears to be concentrated in interneurons in addition to principalcells, and in all regions 8t/9q expression appears to be concentrated inneurons as apposed to glial cells.

[0208] Single- and double-label immunohistochemistry revealed that thePCIP and Kv4 polypeptides are precisely colocalized in many of the celltypes and brain regions where PCIP and Kv4 mRNAs are coexpressed. Forexample, 9qm colocalized with Kv4.2 in the somata and dendrites ofhippocampal granule and pyramidal cells, neurons in the medial habenularnucleus and in cerebellar basket cells, while 1v colocalized with Kv4.3in layer II neurons of posterior cingulate cortex, hippocampalinterneurons, and in a subset of cerebellar granule cells.Immunoprecipitation analyses indicated that 1v and 9qm are coassociatedwith Kv4 α-subunits in rat brain membranes.

Example 7 Co-association OF 1V AND Kv4.3 in COS Cells

[0209] COS1 cells were transiently transfected with rat Kv4.3 alone, ratKv4.3+rat 1v, and rat 1v alone using the lipofectamine plus procedureessentially as described by the manufacturer (Boehringer Mannheim).Forty-eight hours after the transfection, cells were washed, fixed, andprocessed for immunofluorescent visualization as described previously(Bekele-Arcuri et al. (1996) Neuropharmacology, 35:851-865).Affinity-purified rabbit polyclonal or mouse monoclonal antibodies tothe Kv4.3 or rat 1v protein were used for immunofluorescent detection ofthe target proteins. Cells transfected with 1v alone and stained with1v-specific revealed that 1v is diffusely distributed throughout thecytoplasm of transiently transfected cells, as expected for acytoplasmic protein. Cells transiently transfected with Kv4.3 alone andstained with antibodies specific for Kv4.3 revealed that although muchof the expressed channel protein is trapped within intracellularorganelles, Kv4.3 expression is also concentrated at the outer marginsof the cell and is presumed to be associated with the cell membrane.When the 1v protein is coexpressed with Kv4.3 in COS1 cells, thesubcellular distribution of 1v is dramatically different than it is incells transfected with 1v alone. In cells cotransfected with 1v andKv4.3, 1v protein expression appears to be trapped in intracellularorganelles and becomes concentrated at the outer margins of the cell.Double-label immunofluorescence of these co-transfected cells indicatesthat the pattern of 1v immunofluorecence is identical that for Kv4.3,indicating that these two proteins are extensively colocalized incotransfected cells. Moreover, the extensive and dramatic change in thesubcellular distribution of 1v when it is coexpressed with Kv4.3suggests that the proteins coassociate when they are coexpressed.

[0210] To further demonstrate that 1v and Kv4.3 directly associate incotransfected cells, COS1 cells were cotransfected with 1v and Kv4.3cDNAs as described above. The cells were then lysed in buffer containingdetergent and protease inhibitors, and prepared for immunoprecipitationreactions essentially as described previously (Nakahira et al. (1996) J.Biol. Chem., 271:7084-7089). Antibodies specific for 1v or Kv4.3 wereused to immunoprecipitate the corresponding polypeptide from thetransfected cell lysates essentially as described in Nakahira et al.(1996) J. Biol. Chem., 271:7084-7089 and in Harlow E. and Lane, D.,Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory, c1988.The products resulting from the immunoprecipitation were sizefractionated by SDS-PAGE and transferred to nitrocellulose filters usingstandard procedures. Immunoblots performed using Kv4.3-specificantibodies revealed that 1v co-immunoprecipitates Kv4.3 from lysatesprepared from co-transfected cells, indicating that the two proteins aretightly co-associated. Taken together, these data suggest that 1v maypromote the transit of the Kv4.3 subunits to the cell surface, and thatthis chaperone-like effect may underlie the enhancement of Kv4 currentdensity by 1v.

Example 8 Electrophysiological Characterization of PCIPs

[0211] Currents flowing through rKv4.2 were measuredelectrophysiologically after transiently transfecting the channels (withor without rat 1v) in CHO cells or microinjecting in vitro transcribedmRNA into Xenopus oocytes. Currents in CHO cells were measured using thepatch-clamp technique (Hamill et al. 1981. Pfluegers Arch. 391:85-100),while currents in oocytes were measured with two-electrode voltageclamp. CHO cells were transiently-transfected with cDNA using the DOTAPlipofection method as described by the manufacturer. (BoehringerMannheim, Inc.). Transfected cells were identified by cotransfectingenhanced GFP along with the genes of interest and subsequentlydetermining if the cells contained green GFP fluorescence.Alternatively, oocytes were injected with 1-3 ng/oocyte cRNA which wasprepared using standard in vitro transcription techniques (Sambrook etal. 1989. Molecular Cloning: a laboratory manual, Cold Spring HarborPress). When CHO cells were transfected with 1 μg rKv4.2 cDNA, currentlevels averaged about 539 pA/cell, or 23.1 pA/pF (Table 2). When 1v wascoexpressed with rKv4.2, however, the current amplitude increased by 8.5fold to an average of 3076 pA/cell or 197.2 pA/pF (see below). TABLE 2CHO Oocytes Oocytes rKv4.2 hKv4.3 hKv1.4 Parameter rKv4.2 + 1v hKv4.3 +1v hKv1.4 + 1v Peak Current 538.8 3076.3 7.7 A 18.1 A 8.3 A 6.5 A(pA/cell) Peak Current 3.1 197.2 — — — — (pA/pF) Inactivation 0.4 90.958.5 137.0 52.3 57.8 time constant (ms, at 40 mV) Recovery from 47.339.7 327.0 34.5 132.6, 210.7, Inactivation time constant (ms, 666.8821.9 at −80 mV) Activation 13.1 −15.9 −19.2 −45.5 −21.0 −13.5V_(1/2)(mV) Steady-state −54.1 −59.7 −57.4 −56.8 −47.5 −48.1Inactivation V_(1/2)(mV)

[0212] Coexpression of 1v also caused a number of changes in otherkinetic parameters of the rKv4.2 current. The voltage at which half ofthe channels are activated is a measure of the voltage dependence of thechannels. This half activation voltage for rKv4.2 was relatively high at13 mV. Coexpression of 1v with rKv4.2 shifted the half activationvoltage by 29 mV to the more negative potential of -16 mV (Table 2). Thevoltage at which channels inactivate during a long (1 second) pulse onlyshifted slightly from −54 to -60 mV with 1v coexpression.

[0213] The modulatory effects observed with 1v coexpression were notlimited to the rKv4.2 channel or to CHO cells. A similar modulation by1v of hKv4.3 expressed in Xenopus oocytes has also been observed (seeTable 2). Co-injection of 1v into oocytes induced an increase in hKv4.3current, a slowing of inactivation, a speeding of the recovery frominactivation, and a leftward shift in the activation curve. The effectsof 1v, however, did not translate to all inactivating channel types, asthe inactivating hKv1.4 channel was not effected by coinjection of 1vmRNA into oocytes (Table 2).

[0214] Co-expression of 1v or 9qm with Kv4 α-subunits in CHO cells orXenopus oocytes revealed that the corresponding polypeptidesco-associate with Kv4 subunits and dramatically modulate the currentdensity, rate of inactivation and rate of recovery from inactivation ofKv4 channels.

[0215] Deletion of the N-terminus of the two PCIP proteins 1v and 9qm(the first 31 amino acids were deleted from 1v and the first 67 aminoacids were deleted from 9qm) did not alter their modulatory actions onKv4.2 current amplitude and kinetics when co-expressed in CHO cells.Thus, the variable N-terminus of these genes is not responsible fortheir modulatory actions on Kv4 channels. Point mutations were thenconstructed in the EF-hand domains of the 1v gene to remove its putativeability to bind calcium. Two different mutants were created: one haspoint mutations in the first two EF hands (D₁₉₉ to A, G₁₀₄ to A, D₁₃₅ toA, and G₁₄₀ to A) and the other one has point muations in all three EFhands (D₁₉₉ to A, G₁₀₄ to A, D₁₃₅ to A, G₁₄₀ to A, D₁₈₃ to A, and G₁₈₈to A). These mutations had a large effect on the modulatory function ofthis gene; co-expression with Kv4.2 produced a much smaller increase incurrent than the wild type 1v and very little effect on the otherkinetic parameters of the channel. Thus, the EF-hand, or putative Ca²⁺binding domains, of 1v appear to have a critical role in the modulatoryactions of the PCIP genes.

Example 9 Characterization of the PCIP Proteins

[0216] In this example, the amino acid sequences of the PCIP proteinswere compared to amino acid sequences of known proteins and variousmotifs were identified.

[0217] The 1v polypeptide, the amino acid sequence of which is shown inSEQ ID NO:3 is a novel polypeptide which includes 216 amino acidresidues. Domains that are putatively involved in calcium binding(Linse, S. and Forsen, S. (1995) Advances in Second Messenger andPhosphoprotein Research 30, Chapter 3, p89-151, edited by Means, A R.,Raven Press, Ltd., New York), were identified by sequence alignment (seeFIG. 21).

[0218] The 8t polypeptide, the amino acid sequence of which is shown inSEQ ID NO:30 is a novel polypeptide which includes 225 amino acidresidues. Calcium binding domains that are putatively involved incalcium binding (Linse, S. and Forsen, S. (1995) Advances in SecondMessenger and Phosphoprotein Research 30, Chapter 3, p89-151, edited byMeans, A R., Raven Press, Ltd., New York), were identified by sequencealignment (see FIG. 21).

[0219] The 9q polypeptide is a novel polypeptide which includes calciumbinding domains that are putatively involved in calcium binding (Linse,S. and Forsen, S. (1995) Advances in Second Messenger and PhosphoproteinResearch 30, Chapter 3, p89-151, edited by Means, A R., Raven Press,Ltd., New York (see FIG. 21).

[0220] The p19 polypeptide is a novel polypeptide which includes calciumbinding domains that are putatively involved in calcium binding (Linse,S. and Forsen, S. (1995) Advances in Second Messenger and PhosphoproteinResearch 30, Chapter 3, p89-151, edited by Means, A R., Raven Press,Ltd., New York (see FIG. 21).

[0221] A BLASTN 2.0.7 search (Altschul et al. (1990) J. Mol. Biol.215:403) of the nucleotide sequence of rat 1vl revealed that the rat 1vlis similar to the rat cDNA clone RMUAH89 (Accession Number AA849706).The rat 1 vl nucleic acid molecule is 98% identical to the rat cDNAclone RMUAH89 (Accession Number AA849706) over nucleotides 1063 to 1488.

[0222] A BLASTN 2.0.7 search (Altschul et al. (1990) J. Mol. Biol.215:403) of the nucleotide sequence of human 9ql revealed that the human9ql is similar to the human cDNA clone 1309405 (Accession NumberAA757119). The human 9 ql nucleic acid molecule is 98% identical to thehuman cDNA clone 1309405 (Accession Number AA757119) over nucleotides937 to 1405.

[0223] A BLASTN 2.0.7 search (Altschul et al. (1990) J. Mol. Biol.215:403) of the nucleotide sequence of mouse P19 revealed that the mouseP19 is similar to the Mus musculus cDNA clone MNCb-7005 (AccessionNumber AU035979). The mouse P19 nucleic acid molecule is 98% identicalto the Mus musculus cDNA clone MNCb-7005 (Accession Number AU035979)over nucleotides 1 to 583.

Example 10 Expression of Recombinant PCIP Proteins in Bacterial Cells

[0224] In this example, PCIP is expressed as a recombinantglutathione-S-transferase (GST) fusion polypeptide in E. coli and thefusion polypeptide is isolated and characterized. Specifically, PCIP isfused to GST and this fusion polypeptide is expressed in E. coli, e.g.,strain BI21. Expression of the GST-PCIP fusion protein in BI21 isinduced with IPTG. The recombinant fusion polypeptide is purified fromcrude bacterial lysates of the induced BI21 strain by affinitychromatography on glutathione beads. Using polyacrylamide gelelectrophoretic analysis of the polypeptide purified from the bacteriallysates, the molecular weight of the resultant fusion polypeptide isdetermined.

[0225] Rat 1v and 9ql were cloned into pGEX-6p-2 (Pharmacia). Theresulting recombinant fusion proteins were expressed in E. coli cellsand purified following art known methods (described in, for example,Current Protocols in Molecular Biology, eds. Ausubel et al. John Wiley &Sons: 1992). The identities of the purified proteins were verified bywestern blot analysis using antibodies raised against peptide epitopesof rat 1v and 9ql.

Example 11 Expression of Recombinant PCIP Proteins in COS Cells

[0226] To express the PCIP gene in COS cells, the pcDNA/Amp vector byInvitrogen Corporation (San Diego, Calif.) is used. This vector containsan SV40 origin of replication, an ampicillin resistance gene, an E. colireplication origin, a CMV promoter followed by a polylinker region, andan SV40 intron and polyadenylation site. A DNA fragment encoding theentire PCIP protein and an HA tag (Wilson et al. (1984) Cell 37:767) ora FLAG tag fused in-frame to its 3′ end of the fragment is cloned intothe polylinker region of the vector, thereby placing the expression ofthe recombinant protein under the control of the CMV promoter.

[0227] To construct the plasmid, the PCIP DNA sequence is amplified byPCR using two primers. The 5′ primer contains the restriction site ofinterest followed by approximately twenty nucleotides of the PCIP codingsequence starting from the initiation codon; the 3′ end sequencecontains complementary sequences to the other restriction site ofinterest, a translation stop codon, the HA tag or FLAG tag and the last20 nucleotides of the PCIP coding sequence. The PCR amplified fragmentand the pCDNA/Amp vector are digested with the appropriate restrictionenzymes and the vector is dephosphorylated using the CIAP enzyme (NewEngland Biolabs, Beverly, Mass.). Preferably the two restriction siteschosen are different so that the PCIP gene is inserted in the correctorientation. The ligation mixture is transformed into E. coli cells(strains HB101, DH5a, SURE, available from Stratagene Cloning Systems,La Jolla, Calif., can be used), the transformed culture is plated onampicillin media plates, and resistant colonies are selected. PlasmidDNA is isolated from transformants and examined by restriction analysisfor the presence of the correct fragment.

[0228] COS cells are subsequently transfected with the PCIP-pcDNA/Ampplasmid DNA using the calcium phosphate or calcium chlorideco-precipitation methods, DEAE-dextran-mediated transfection,lipofection, or electroporation. Other suitable methods for transfectinghost cells can be found in Sambrook, J., Fritsh, E. F., and Maniatis, T.Molecular Cloning: A Laboratory Manual. 2nd, ed., Cold Spring HarborLaboratory, Cold Spring Harbor Laboratory Press, Cold Spring Harbor,N.Y., 1989. The expression of the PCIP polypeptide is detected byradiolabelling (³⁵S-methionine or ³⁵S-cysteine available from NEN,Boston, Mass., can be used) and immunoprecipitation (Harlow, E. andLane, D. Antibodies: A Laboratory Manual, Cold Spring Harbor LaboratoryPress, Cold Spring Harbor, N.Y., 1988) using an HA specific monoclonalantibody. Briefly, the cells are labelled for 8 hours with³⁵S-methionine (or ³⁵S-cysteine). The culture media are then collectedand the cells are lysed using detergents (RIPA buffer, 150 mM NaCl, 1%NP-40, 0.1% SDS, 0.5% DOC, 50 mM Tris, pH 7.5). Both the cell lysate andthe culture media are precipitated with an HA specific monoclonalantibody. Precipitated polypeptides are then analyzed by SDS-PAGE.

[0229] Alternatively, DNA containing the PCIP coding sequence is cloneddirectly into the polylinker of the pCDNA/Amp vector using theappropriate restriction sites. The resulting plasmid is transfected intoCOS cells in the manner described above, and the expression of the PCIPpolypeptide is detected by radiolabelling and immunoprecipitation usinga PCIP specific monoclonal antibody.

[0230] Rat 1v was cloned into the mammalian expresssion vector pRBG4.Transfections into COS cells were performed using LipofectAmine Plus(Gibco BRL) following the manufacturer's instructions. The expressed 1vprotein was detected by immunocytochemistry and/or western blot analysisusing antibodies raised against 1v in rabbits or mice.

Example 12 Identification and Characterization of Human Full Length p19

[0231] The human full length p19 sequence was identified using RACE PCR.The sequence of p19 (also referred to as KChIP3) is shown in FIG. 16.The amino acid sequence of human p19 is 92% identical to the mouse p19gene (SEQ ID NO:35).

[0232] TBLASTN searches using the protein sequence of human p19 revealedthat human p19 is homologous to two sequences, Calsenilin (described in(1998) Nature Medicine 4: 1177-1181) and DREAM (described in Carrion etal. (1999) Nature 398:80-84). Human p19 is 100% identical at thenucleotide level to Calsenilin (but extends 3′ to the publishedsequence) and 99% identical at the nucleotide level to DREAM.

[0233] The ability of p19 (as well as other PCIP family members) toco-localize with presenilin and act as transcription factors isdetermined using art known techniques such as northern blots, in situhybridization, β-gal assays, DNA mobility assays (described in, forexample, Carrion et al. (1999) Nature 398:80) and DNA mobilitysupershift assays, using antibodies specific for KchIPs.

[0234] Other assays suitable for evaluating the association of PCIPfamily members with presenilins is co-immunoprecipitation (described in,for example, Buxbaum et al. (1998) Nature Medicine 4:1177).

Example 13 Identification and Characterization of Monkey KChIP4

[0235] In this example, the identification and characterization of thegenes encoding monkey KChIP4a (jlkbd352e01t1) and alternatively splicedmonkey KChIP4b (jlkbb231c04t1), KChIP4c (jlkxa053c02), and KChIP4d(jlkx015b10) is described. TBLASTN searches in proprietary databaseswith the sequence of the known PCIP family members, lead to theidentification of four clones jlkbb231c04t1, jlkbd352e01t1, jlkxa053c02,and jlkx015b10. The four monkey clones were obtained and sequenced.

[0236] The sequences of proprietary monkey clones jlkbb231c04t1 andjlkbd352e01t1 were found to correspond to alternately spliced variantsof an additional PCIP family member, referred to herein as KChIP4. Clonejlkbb231c04t1 contains a 822 bp deletion relative to jlkbd352e01t1presumably due to splicing out of an exon), resulting in the loss of thefinal EF hand domain. In clone jlkbd352e01t1, the final EF hand domainis preserved, and the C-terminus is highly homologous to that of PCIPfamily members 1v, 9ql, and p19. Overall identity in the homologousC-termini among KChIP4, 1v, 9ql, and p19 ranged from 71%-80% at theamino acid level (alignments were performed using the CLUSTALW).

[0237] Monkey KChIP4c and KChIP4d were discovered by BLASTN search usingmonkey KChIP4a as a query for searching a proprietary database.

[0238] The nucleotide sequence of the monkey KChIP4a cDNA and thepredicted amino acid sequence of the KChIP4a polypeptide are shown inFIG. 23 and in SEQ ID NOs:48 and 49, respectively.

[0239] The nucleotide sequence of the monkey KChIP4b cDNA and thepredicted amino acid sequence of the KChIP4b polypeptide are shown inFIG. 24 and in SEQ ID NOs:50 and 51, respectively.

[0240] The nucleotide sequence of the monkey KChIP4c cDNA and thepredicted amino acid sequence of the KChIP4c polypeptide are shown inFIG. 35 and in SEQ ID NOs:69 and 70, respectively.

[0241] The nucleotide sequence of the monkey KChIP4d cDNA and thepredicted amino acid sequence of the KChIP4d polypeptide are shown inFIG. 36 and in SEQ ID NOs:71 and 72, respectively.

[0242]FIG. 37 depicts an alignment of the protein sequences of KChIP4a,KChIP4b, KChIP4c, and KChIP4d.

Example 14 Identification and Characterization of Human and Rat 33b07

[0243] In this example, the identification and characterization of thegenes encoding rat and human 33b07 is described. Partial rat 33b07(clone name 9o) was isolated as a positive clone from the yeasttwo-hybrid screen described above, using rKv4.3N as bait. The fulllength rat 33b07 clone was identified by mining of proprietarydatabases.

[0244] The nucleotide sequence of the full length rat 33b07 cDNA and thepredicted amino acid sequence of the rat 33b07 polypeptide are shown inFIG. 26 and in SEQ ID NOs:52 and 53, respectively. The rat 33b07 cDNAencodes a protein having a molecular weight of approximately 44.7 kD andwhich is 407 amino acid residues in length.

[0245] Rat 33b07 binds rKv4.3N and rKv4.2N with slight preference forrKv4.2N in yeast 2-hybrid assays. In contrast, rat 33b07 does not bindrKv1.1N, indicating that the rat 33b07-Kv4N interaction is specific.

[0246] Rat 33b07 is expressed predominantly in the brain as determinedby northern blot analysis.

[0247] The human 33b07 ortholog (clone 106d5) was also identified bymining of proprietary databases. The nucleotide sequence of the fulllength human 33b07 cDNA and the predicted amino acid sequence of thehuman 33b07 polypeptide are shown in FIG. 27 and in SEQ ID NOs:54 and55, respectively. The human 33b07 cDNA encodes a protein having amolecular weight of approximately 45.1 kD and which is 414 amino acidresidues in length.

[0248] Human 33b07 is 99% identical to the human KIAA0721 protein(GenBank Accession Number: ABOL 8264) at the amino acid level. However,GenBank Accession Number: AB018264 does not have a functionalannotation. Human 33b07 is also homologous to Testes-specific(Y-encoded) proteins (TSP(Y)s), SET, and Nucleosome Assembly Proteins(NAPs). The human 33b07 is 38% identical to human SET protein (GenBankAccession Number Q01105=U51924) over amino acids 204 to 337 and 46%identical over amino acids 334 to 387.

[0249] Human SET is also called HLA-DR associated protein II (PHAPII)(Hoppe-Seyler (1994) Biol. Chem. 375:113-126) and in some cases isassociated with acute undifferentiated leukemia (AUL) as a result of atranslocation event resulting in the formation of a SET-CAN fusion gene(Von Lindern M. et al. (1992) Mol. Cell. Biol. 12:3346-3355). Analternative spliced form of SET is also called Template ActivatingFactor-I alpha (TAF). TAF is found to be associated with myeloidleukemogenesis (Nagata K. et al. (1995) Proc. Natl. Acad. Sci. U.S.A. 92(10), 4279-4283). Human SET is also a potent protein inhibitor ofphosphatase 2A (Adachi Y. et al. (1994) J. Biol. Chem. 269:2258-2262).NAPs may be involved in modulating chromatin formation and contribute toregulation of cell proliferation (Simon H. U. et al. (1994) Biochem. J.297, 389-397).

[0250] Thus, due to its homology to the above identified proteins, 33b07may function as a protein inhibitor of phosphatase, an oncogene, and/ora chromatin modulator. The homology of 33b07 to SET, a proteinphosphatase inhibitor, is of particular interest. Many channels, inparticular the Kv4 channels (with which 33b07 is associated), are knownto be regulated by phosphorylation by PKC and PKA ((1998) J Neuroscience18(10):3521-3528; Am J Physiol 273: H1775-86 (1997)). Thus, 33b07 maymodulate Kv4 activity by regulating the phosphorylation status of thepotassium channel.

Example 15 Identification and Characterization of Rat 1p

[0251] In this example, the identification and characterization of thegene encoding rat 1p is described. Partial rat 1p was isolated as apositive clone from the yeast two-hybrid screen described above, usingrKv4.3N as a bait.

[0252] The nucleotide sequence of the partial length rat 1p cDNA and thepredicted amino acid sequence of the rat 1p polypeptide are shown inFIG. 28 and in SEQ ID NOs:56 and 57, respectively. The rat 1p cDNAencodes a protein having a molecular weight of approximately 28.6 kD andwhich is 267 amino acid residues in length.

[0253] Rat 1p binds rKv4.3N and rKv4.2N with slight preference forrKv4.3N in yeast two-hybrid assays. In contrast, 1p does not bindrKv1.1N, indicating that the 11p-Kv4N interaction is specific.

[0254] Rat 1p is predominantly expressed in the brain as determined bynorthern blot analysis.

[0255] A BLASTP 1.4 search, using a score of 100 and a word length of 3(Altschul et al. (1990) J. Mol. Biol. 215:403) of the amino acidsequences of rat 1p revealed that rat 1p is similar to the human Restin(GenBank Accession Number P30622; also named cytoplasmic linkerprotein-170 alpha-2 (CLIP-170), M97501)). The rat 1p protein is 58%identical to the human Restin over amino acid residues 105 to 182, 55%identical to the human Restin over amino acid residues 115 to 186, 22%identical to the human Restin over amino acid residues 173 to 246, 22%identical to the human Restin over amino acid residues 169 to 218, and58% identical to the human Restin over amino acid residues 217 to 228.

[0256] Restin is also named Reed-Sternberg intermediate filamentassociated protein. Reed-Sternberg cells are the tumoral cellsdiagnostic for Hodgkin's disease. It is suggested that Restinoverexpression may be a contributing factor in the progression ofHodgkin's disease (Bilbe G. et al. (1992) EMBO J. 11:2103-13) and Restinappears to be an intermediate filament associated protein that linksendocytic vesicles to microtubules (Pierre P, et al. (1992) Cell 70 (6),887-900).

[0257] The cytoskeleton regulates the activity of potassium channels(see, for example, Honore E, et al. (1992) EMBO J. 11:2465-2471 andLevin G, et al. (1996) J. Biol. Chem. 271:29321-29328), as well as theactivity of other channels, e.g., Ca⁺⁺ channels (Johnson B. D. et al.(1993) Neuron 10:797-804); or Na⁺ channels (Fukuda J. et al. (1981)Nature 294:82-85).

[0258] Accordingly, based on its homology to the Restin protein, the rat1p protein may be associated with the cytoskeleton and may modulate theactivity of potassium channels, e.g., Kv4, via its association to thecytoskeleton.

Example 16 Identification and Characterization of Rat 7s

[0259] In this example, the identification and characterization of thegene encoding rat 7s is described. Partial rat 7s was isolated as apositive clone from the yeast two-hybrid screen described above, usingrKv4.3N as a bait. Rat 7s is the rat ortholog of the human vacuolarH(+)-ATPase catalytic subunit A (Accession Number P38606 and B46091)described in, for example, van Hille B. et al. (1993) J. Biol. Chem. 268(10), 7075-7080.

[0260] The nucleotide sequence of the partial length rat 7s cDNA and thepredicted amino acid sequence of the rat 7s polypeptide are shown inFIG. 29 and in SEQ ID NOs:58 and 59, respectively. The rat 7s cDNAencodes a protein having a molecular weight of approximately 28.6 kD andwhich is 270 amino acid residues in length.

[0261] Rat 7s binds rKv4.3N and rKv4.2N with preference for rKv4.3N inyeast two-hybrid assays. In contrast, 7s does not bind rKv1.1N,indicating that the 7s-Kv4N interaction is specific.

[0262] Rat 7s is expressed at significantly higher levels in the brainand the kidney than in the lung, liver, heart, testes, and skeletalmuscle, as determined by northern blot analysis.

Example 17 Identification and Characterization of Rat 29x and 25r

[0263] In this example, the identification and characterization of thegene encoding rat 29x is described. Rat 29x was isolated as a positiveclone from the yeast two-hybrid screen described above, using rKv4.3N asa bait. Rat 25r is a splice variant of 29x. They differ in the 5′untranslated region, but are identical in the coding region and at theamino acid level.

[0264] The nucleotide sequence of the rat 29x cDNA and the predictedamino acid sequence of the rat 29x polypeptide are shown in FIG. 30 andin SEQ ID NOs:60 and 61, respectively. The rat 29x cDNA encodes aprotein having a molecular weight of approximately 40.4 kD and which is351 amino acid residues in length.

[0265] The nucleotide sequence of the rat 25r cDNA is shown in FIG. 31and in SEQ ID NO:62. The rat 25r cDNA encodes a protein having amolecular weight of approximately 40.4 kD and which is 351 amino acidresidues in length.

[0266] Rat 29x is expressed in the spleen, lung, kidney, heart, brain,testes, skeletal muscle and liver, with the highest level of expressionbeing in the spleen and the lowest being in the liver.

[0267] Rat 29x binds rKv4.3N and rKv4.2N with slight preference forrKv4.3N in yeast two-hybrid assays. In contrast, 29x does not bindrKv1.1N, indicating that the 29x-Kv4N interaction is specific.

[0268] Rat 29x is identical at the amino acid level to rat SOCS-1(Suppressor Of Cytokine Signaling) described in Starr R. et al. (1997)Nature 387:917-921; to JAB described in Endo T. A. et al. (1997) Nature387:921-924; and to SSI-1 (STAT-induced STAT inhibitor-1) described inNaka T. et al. (1997) Nature 387:924-928. These proteins arecharacterized in that they have an SH2 domain, bind to and inhibit JAKkinase, and, as a result, regulate cytokine signaling.

[0269] As used herein, the term “SH2 domain”, also referred to a SrcHomology 2 domain, includes a protein domain of about 100 amino acids inlength which is involved in binding of phosphotyrosine residues, e.g.,phosphotyrosine residues in other proteins. The target site is called anSH2-binding site. The SH2 domain has a conserved 3D structure consistingof two alpha helices and six to seven beta-strands. The core of the SH2domain is formed by a continuous beta-meander composed of two connectedbeta-sheets (Kuriyan J. et al. (1997) Curr. Opin. Struct. Biol.3:828-837). SH2 domains function as regulatory modules of intracellularsignaling cascades by interacting with high affinity tophosphotyrosine-containing target peptides in a sequence-specific andstrictly phosphorylation-dependent manner (Pawson T. (1995) Nature373:573-580). Some proteins contain multiple SH2 domains, whichincreases their affinity for binding to phosphoproteins or confers theability to bind to different phosphoproteins. Rat 29x contains an SH2domain at amino acid residues 219-308 of SEQ ID NO:61.

[0270] Tyrosine phosphorylation regulates potassium channel activity(Prevarskaya N.B. et al. (1995) J. Biol. Chem. 270:24292-24299). JAKkinase phoshorylates proteins at tyrosines and is implicated in theregulation of channel activity (Prevarskaya N.B. et al. supra).Accordingly, based on its homology to SOCS-1, JAB, and SSI-1, rat 29xmay modulate the activity of potassium channels, e.g., Kv4, bymodulating JAK kinase activity.

Example 18 Identification and Characterization of Rat 5p

[0271] In this example, the identification and characterization of thegene encoding rat 5p is described. Rat 5p was isolated as a positiveclone from the yeast two-hybrid screen described above, using rKv4.3N asa bait.

[0272] The nucleotide sequence of the rat 5pc DNA and the predictedamino acid sequence of the rat 5p polypeptide are shown in FIG. 32 andin SEQ ID NOs:63 and 64, respectively. The rat 5p cDNA encodes a proteinhaving a molecular weight of approximately 11.1 kD and which is 95 aminoacid residues in length.

[0273] Rat 5p binds rKv4.3N and rKv4.2N with similar strength in yeasttwo-hybrid assays. In contrast, 5p does not bind rKv1.1N, indicatingthat the 5p-Kv4N interaction is specific.

[0274] Rat 5p is expressed in the spleen, lung, skeletal muscle, heart,kidney, brain, liver, and testes, as determined by northern blotanalysis.

[0275] The rat 5p is identical to rat Calpactin I light chain or P10(Accession Number P05943). P10 binds and induces the dimerization ofannexin II (p36). P10 may function as a regulator of proteinphosphorylation in that the p36 monomer is the preferred target of atyrosine-specific kinase (Masiakowski P. et al. (1998) Proc. Natl. Acad.Sci. U.S.A. 85 (4): 1277-1281).

[0276] Tyrosine phosphorylation regulates the activity of potassiumchannels (Prevarskaya N. B. et al. supra). Thus, due to its identity toP10, rat 5p may modulate the activity of potassium channels, e.g., Kv4,by modulating the activity of a tyrosine-specific kinase.

Example 19 Identification and Characterization of Rat 7q

[0277] In this example, the identification and characterization of thegene encoding rat 7q is described. Rat 7q was isolated as a positiveclone from the yeast two-hybrid screen described above, using rKv4.3N asa bait. Full length rat 7q was obtained by RACE PCR.

[0278] The nucleotide sequence of the rat 7q cDNA and the predictedamino acid sequence of the rat 7q polypeptide are shown in FIG. 33 andin SEQ ID NOs:65 and 66, respectively. The rat 7q cDNA encodes a proteinhaving a molecular weight of approximately 23.5 kD and which is 212amino acid residues in length.

[0279] Rat 7q binds rKv4.3N and rKv4.2N with same strength in yeasttwo-hybrid assays. In contrast, 7q does not bind rKv1.1N, indicatingthat the 7q-Kv4N interaction is specific.

[0280] Rat 7q is expressed in the heart, brain, spleen, lung, liver,skeletal muscle, kidney, and testes, as determined by northern blotanalysis.

[0281] Rat 7q is identical to RAB2 (rat RAS-related protein, AccessionNumber P05712) at the amino acid level. RAB2 appears to be involved invesicular traffic and protein transport (Touchot N. et al. (1987) Proc.Natl. Acad. Sci. U.S.A. 84 (23):8210-8214). Accordingly, based on itshomology to RAB2, rat 7q may be involved in potassium channel, e.g.,Kv4, trafficking.

Example 20 Identification and Characterization of Rat 19r

[0282] In this example, the identification and characterization of thegene encoding rat 19r is described. Partial rat 19r was isolated as apositive clone from the yeast two-hybrid screen described above, usingrKv4.3N as a bait. Full length rat 19r was obtained by RACE PCR.

[0283] The nucleotide sequence of the rat 19r cDNA and the predictedamino acid sequence of the rat 19r polypeptide are shown in FIG. 34 andin SEQ ID NOs:67 and 68, respectively. The rat 19r cDNA encodes aprotein having a molecular weight of approximately 31.9 kD and which is271 amino acid residues in length.

[0284] Rat 19r is expressed in the heart, brain, spleen, lung, liver,skeletal muscle, kidney, and testes, as determined by northern blotanalysis.

[0285] Rat 19r binds rKv4.3N and rKv4.2N with slight preference forrKv4.3N in yeast two-hybrid assays. In contrast, 19r does not bindrKv1.1N, indicating that the 19r-Kv4N interaction is specific.

[0286] Rat 19r is identical to Rat phosphatidylinositol (PTDINS)transfer protein alpha (PTDINSTP, Accession Number M25758 or P16446)described in Dickeson S. K. et al. (1989) J. Biol. Chem.264:16557-16564. PTDINSTP is believed to be involved in phospholipaseC-beta (PLC-beta) signaling, phosphatidylinositol transfer protein(PtdIns-TP) synthesis, secrettory vesicle formation, and enhancement ofphosphatidylinositol 3-kinase (PtdIns 3-kinase) activity (Cunningham E.et al. (1995) Curr. Biol. 5 (7):775-783; (1995) Nature 377(6549):544-547; and Panaretou C. et al. (1997) J. Biol. Chem. 272 (4):2477-2485).

[0287] Accordingly, based on its homology with PTDINSTP, rat 19r maymodulate potassium channel, e.g., Kv4, activity via the PLC-betasignaling pathway and/or the PtdIns 3-kinase signaling pathway. Rat p19rmay also be involved in potassium channel, e.g., Kv4, trafficking.

EQUIVALENTS

[0288] Those skilled in the art will recognize, or be able to ascertainusing no more than routine experimentation, many equivalents to thespecific embodiments of the invention described herein. Such equivalentsare intended to be encompassed by the following claims.

1 72 1 1463 DNA Homo sapiens CDS (225)..(872) 1 gaatagcccc ctttcacttctgagtccctg catgtgcggg gctgaagaag gaagccagaa 60 gcctcctagc ctcgcctccacgtttgctga ataccaagct gcaggcgagc tgccgggcgc 120 ttttctctcc tccaattcagagtagacaaa ccacggggat ttctttccag ggtaggggag 180 gggccgggcc cggggtcccaactcgcactc aagtcttcgc tgcc atg ggg gcc gtc 236 Met Gly Ala Val 1 atg ggcacc ttc tca tct ctg caa acc aaa caa agg cga ccc tcg aaa 284 Met Gly ThrPhe Ser Ser Leu Gln Thr Lys Gln Arg Arg Pro Ser Lys 5 10 15 20 gat aagatt gaa gat gag ctg gag atg acc atg gtt tgc cat cgg ccc 332 Asp Lys IleGlu Asp Glu Leu Glu Met Thr Met Val Cys His Arg Pro 25 30 35 gag gga ctggag cag ctc gag gcc cag acc aac ttc acc aag agg gag 380 Glu Gly Leu GluGln Leu Glu Ala Gln Thr Asn Phe Thr Lys Arg Glu 40 45 50 ctg cag gtc ctttat cga ggc ttc aaa aat gag tgc ccc agt ggt gtg 428 Leu Gln Val Leu TyrArg Gly Phe Lys Asn Glu Cys Pro Ser Gly Val 55 60 65 gtc aac gaa gac acattc aag cag atc tat gct cag ttt ttc cct cat 476 Val Asn Glu Asp Thr PheLys Gln Ile Tyr Ala Gln Phe Phe Pro His 70 75 80 gga gat gcc agc acg tatgcc cat tac ctc ttc aat gcc ttc gac acc 524 Gly Asp Ala Ser Thr Tyr AlaHis Tyr Leu Phe Asn Ala Phe Asp Thr 85 90 95 100 act cag aca ggc tcc gtgaag ttc gag gac ttt gta acc gct ctg tcg 572 Thr Gln Thr Gly Ser Val LysPhe Glu Asp Phe Val Thr Ala Leu Ser 105 110 115 att tta ttg aga gga actgtc cac gag aaa cta agg tgg aca ttt aat 620 Ile Leu Leu Arg Gly Thr ValHis Glu Lys Leu Arg Trp Thr Phe Asn 120 125 130 ttg tat gac atc aac aaggac gga tac ata aac aaa gag gag atg atg 668 Leu Tyr Asp Ile Asn Lys AspGly Tyr Ile Asn Lys Glu Glu Met Met 135 140 145 gac att gtc aaa gcc atctat gac atg atg ggg aaa tac aca tat cct 716 Asp Ile Val Lys Ala Ile TyrAsp Met Met Gly Lys Tyr Thr Tyr Pro 150 155 160 gtg ctc aaa gag gac actcca agg cag cat gtg gac gtc ttc ttc cag 764 Val Leu Lys Glu Asp Thr ProArg Gln His Val Asp Val Phe Phe Gln 165 170 175 180 aaa atg gac aaa aataaa gat ggc atc gta act tta gat gaa ttt ctt 812 Lys Met Asp Lys Asn LysAsp Gly Ile Val Thr Leu Asp Glu Phe Leu 185 190 195 gaa tca tgt cag gaggac gac aac atc atg agg tct ctc cag ctg ttt 860 Glu Ser Cys Gln Glu AspAsp Asn Ile Met Arg Ser Leu Gln Leu Phe 200 205 210 caa aat gtc atgtaactggtga cactcagcca ttcagctctc agagacattg 912 Gln Asn Val Met 215tactaaacaa ccaccttaac accctgatct gcccttgttc tgattttaca caccaactct 972tgggacagaa acacctttta cactttggaa gaattctctg ctgaagactt tcttatggaa 1032cccagcatca tgtggctcag tctctgattg ccaactcttc ctctttcttc ttcttgagag 1092agacaagatg aaatttgagt ttgttttgga agcatgctca tctcctcaca ctgctgccct 1152atggaaggtc cctctgctta agcttaaaca gtagtgcaca aaatatgctg cttacgtgcc 1212cccagcccac tgcctccaag tcaggcagac cttggtgaat ctggaagcaa gaggacctga 1272gccagatgca caccatctct gatggcctcc caaaccaatg tgcctgtttc tcttcctttg 1332gtgggaagaa tgagagttat ccagaacaat taggatctgt catgaccaga ttgggagagc 1392cagcacctaa catatgtggg ataggactga attattaagc atgacattgt ctgatgaccc 1452aaactgcccc g 1463 2 216 PRT Homo sapiens 2 Met Gly Ala Val Met Gly ThrPhe Ser Ser Leu Gln Thr Lys Gln Arg 1 5 10 15 Arg Pro Ser Lys Asp LysIle Glu Asp Glu Leu Glu Met Thr Met Val 20 25 30 Cys His Arg Pro Glu GlyLeu Glu Gln Leu Glu Ala Gln Thr Asn Phe 35 40 45 Thr Lys Arg Glu Leu GlnVal Leu Tyr Arg Gly Phe Lys Asn Glu Cys 50 55 60 Pro Ser Gly Val Val AsnGlu Asp Thr Phe Lys Gln Ile Tyr Ala Gln 65 70 75 80 Phe Phe Pro His GlyAsp Ala Ser Thr Tyr Ala His Tyr Leu Phe Asn 85 90 95 Ala Phe Asp Thr ThrGln Thr Gly Ser Val Lys Phe Glu Asp Phe Val 100 105 110 Thr Ala Leu SerIle Leu Leu Arg Gly Thr Val His Glu Lys Leu Arg 115 120 125 Trp Thr PheAsn Leu Tyr Asp Ile Asn Lys Asp Gly Tyr Ile Asn Lys 130 135 140 Glu GluMet Met Asp Ile Val Lys Ala Ile Tyr Asp Met Met Gly Lys 145 150 155 160Tyr Thr Tyr Pro Val Leu Lys Glu Asp Thr Pro Arg Gln His Val Asp 165 170175 Val Phe Phe Gln Lys Met Asp Lys Asn Lys Asp Gly Ile Val Thr Leu 180185 190 Asp Glu Phe Leu Glu Ser Cys Gln Glu Asp Asp Asn Ile Met Arg Ser195 200 205 Leu Gln Leu Phe Gln Asn Val Met 210 215 3 1856 DNA Rattussp. CDS (300)..(1034) 3 ggcacacaac ccctggattc ttcggagaat atgccgtgaggtgttgccaa ttattagttc 60 tcttggctag cagatgttta gggactggtt aagcctttggagaaattacc ttaggaaaac 120 ggggaaataa aagcaaagat taccatgaat tgcaagattacctagcaatt gcaaggtagg 180 aggagagagg tggagggcgg agtagacagg agggagggagaaagtgagag gaagctaggc 240 tggtggaaat aaccctgcac ttggaacagc ggcaaagaagcgcgattttc cagctttaa 299 atg cct gcc cgc gtt ctg ctt gcc tac ccg gga acggag atg ttg acc 347 Met Pro Ala Arg Val Leu Leu Ala Tyr Pro Gly Thr GluMet Leu Thr 1 5 10 15 cag ggc gag tct gaa ggg ctc cag acc ttg ggg atagta gtg gtc ctg 395 Gln Gly Glu Ser Glu Gly Leu Gln Thr Leu Gly Ile ValVal Val Leu 20 25 30 tgt tcc tct ctg aaa cta ctg cac tac ctc ggg ctg attgac ttg tcg 443 Cys Ser Ser Leu Lys Leu Leu His Tyr Leu Gly Leu Ile AspLeu Ser 35 40 45 gat gac aag atc gag gat gat ctg gag atg acc atg gtt tgccat cgg 491 Asp Asp Lys Ile Glu Asp Asp Leu Glu Met Thr Met Val Cys HisArg 50 55 60 cct gag gga ctg gag cag ctt gag gca cag acg aac ttc acc aagaga 539 Pro Glu Gly Leu Glu Gln Leu Glu Ala Gln Thr Asn Phe Thr Lys Arg65 70 75 80 gaa ctg caa gtc ctt tac cgg gga ttc aaa aac gag tgc ccc agtggt 587 Glu Leu Gln Val Leu Tyr Arg Gly Phe Lys Asn Glu Cys Pro Ser Gly85 90 95 gtg gtt aac gaa gag aca ttc aag cag atc tac gct cag ttt ttc cct635 Val Val Asn Glu Glu Thr Phe Lys Gln Ile Tyr Ala Gln Phe Phe Pro 100105 110 cat gga gat gcc agc aca tac gca cat tac ctc ttc aat gcc ttc gac683 His Gly Asp Ala Ser Thr Tyr Ala His Tyr Leu Phe Asn Ala Phe Asp 115120 125 acc acc cag aca ggc tct gta aag ttc gag gac ttt gtg act gct ctg731 Thr Thr Gln Thr Gly Ser Val Lys Phe Glu Asp Phe Val Thr Ala Leu 130135 140 tcg att tta ctg aga gga acg gtc cat gaa aaa ctg agg tgg acg ttt779 Ser Ile Leu Leu Arg Gly Thr Val His Glu Lys Leu Arg Trp Thr Phe 145150 155 160 aat ttg tac gac atc aat aaa gac ggc tac ata aac aaa gag gagatg 827 Asn Leu Tyr Asp Ile Asn Lys Asp Gly Tyr Ile Asn Lys Glu Glu Met165 170 175 atg gac ata gtg aaa gcc atc tat gac atg atg ggg aaa tac acctat 875 Met Asp Ile Val Lys Ala Ile Tyr Asp Met Met Gly Lys Tyr Thr Tyr180 185 190 cct gtg ctc aaa gag gac act ccc agg cag cac gtg gac gtc ttcttc 923 Pro Val Leu Lys Glu Asp Thr Pro Arg Gln His Val Asp Val Phe Phe195 200 205 cag aaa atg gat aaa aat aaa gat ggc att gta acg tta gac gaattt 971 Gln Lys Met Asp Lys Asn Lys Asp Gly Ile Val Thr Leu Asp Glu Phe210 215 220 ctc gag tcc tgt cag gag gat gac aac atc atg agg tct cta cagctg 1019 Leu Glu Ser Cys Gln Glu Asp Asp Asn Ile Met Arg Ser Leu Gln Leu225 230 235 240 ttc caa aat gtc atg taactgagga cactggccat cctgctctcagagacactga 1074 Phe Gln Asn Val Met 245 caaacacctc aatgccctga tctgcccttgttccagtttt acacatcaac tctcgggaca 1134 gaaatacctt ttacactttg gaagaattctctgctgaaga ctttctacaa aacctggcac 1194 cgagtggctc agtctctgat tgccaactcttcctccctcc tcctcttgag agggacgagc 1254 tgaaatccga agtttgtttt ggaagcatgcccatctctcc atgctgctgc tgccctgtgg 1314 aaggcccctc tgcttgagct taaacagtagtgcacagttt tctgcgtata cagatcccca 1374 actcactgcc tctaagtcag gcagaccctgatcaatctga accaaatgtg caccatcctc 1434 cgatggcctc ccaagccaat gtgcctgcttctcttcctct ggtgggaaga aagaacgctc 1494 tacagagcac ttagagctta ccatgaaaatactgggagag gcagcaccta acacatgtag 1554 aataggactg aattattaag catggtggtatcagatgatg caaacagccc atgtcatttt 1614 tttttccaga ggtagggact aataattctcccacactagc acctacgatc atagaacaag 1674 tcttttaaca catccaggag ggaaaccgctgcccagtggt ctatcccttc tctccatccc 1734 ctgctcaagc ccagcactgc atgtctctcccggaaggtcc agaatgcctg tgaaatgctg 1794 taacttttat accctgttat aatcaataaacagaactatt tcgtacaaaa aaaaaaaaaa 1854 aa 1856 4 245 PRT Rattus sp. 4 MetPro Ala Arg Val Leu Leu Ala Tyr Pro Gly Thr Glu Met Leu Thr 1 5 10 15Gln Gly Glu Ser Glu Gly Leu Gln Thr Leu Gly Ile Val Val Val Leu 20 25 30Cys Ser Ser Leu Lys Leu Leu His Tyr Leu Gly Leu Ile Asp Leu Ser 35 40 45Asp Asp Lys Ile Glu Asp Asp Leu Glu Met Thr Met Val Cys His Arg 50 55 60Pro Glu Gly Leu Glu Gln Leu Glu Ala Gln Thr Asn Phe Thr Lys Arg 65 70 7580 Glu Leu Gln Val Leu Tyr Arg Gly Phe Lys Asn Glu Cys Pro Ser Gly 85 9095 Val Val Asn Glu Glu Thr Phe Lys Gln Ile Tyr Ala Gln Phe Phe Pro 100105 110 His Gly Asp Ala Ser Thr Tyr Ala His Tyr Leu Phe Asn Ala Phe Asp115 120 125 Thr Thr Gln Thr Gly Ser Val Lys Phe Glu Asp Phe Val Thr AlaLeu 130 135 140 Ser Ile Leu Leu Arg Gly Thr Val His Glu Lys Leu Arg TrpThr Phe 145 150 155 160 Asn Leu Tyr Asp Ile Asn Lys Asp Gly Tyr Ile AsnLys Glu Glu Met 165 170 175 Met Asp Ile Val Lys Ala Ile Tyr Asp Met MetGly Lys Tyr Thr Tyr 180 185 190 Pro Val Leu Lys Glu Asp Thr Pro Arg GlnHis Val Asp Val Phe Phe 195 200 205 Gln Lys Met Asp Lys Asn Lys Asp GlyIle Val Thr Leu Asp Glu Phe 210 215 220 Leu Glu Ser Cys Gln Glu Asp AspAsn Ile Met Arg Ser Leu Gln Leu 225 230 235 240 Phe Gln Asn Val Met 2455 1907 DNA Mus musculus CDS (477)..(1124) 5 cggccccctg agatccagcccgagcgcggg gcggagcggc cgggtggcag caggggcggg 60 cgggcggagc gcagctcccgcaccgcacgc ggcgcgggct cggcagcctc ggccgtgcgg 120 gcacgccggc cccgtgtccaacatcaggca ggctttgggg ctcggggctc gggcctcgga 180 gaagccagtg gcccggctgggtgcccgcac cggggggcgc ctgtgaaggc tcccgcgagc 240 ctctggccct gggagtcagtgcatgtgcct ggctgaagaa ggcagcagcc acgagctcca 300 ggcgccccgg ccccacgttttctgaatacc aagctgcagg cgagctgctc ggggcttttt 360 tgctttctcg cttttcctctcctccaattc aaagtgggca atccacaccg atttcttttc 420 aggggaggga agagacagggcctggggtcc caagacgcac acaagtcttc gctgcc atg 479 Met 1 ggg gcc gtc atgggc act ttc tcc tcc ctg cag acc aaa caa agg cga 527 Gly Ala Val Met GlyThr Phe Ser Ser Leu Gln Thr Lys Gln Arg Arg 5 10 15 ccc tct aaa gac aagatt gag gat gag cta gag atg acc atg gtt tgc 575 Pro Ser Lys Asp Lys IleGlu Asp Glu Leu Glu Met Thr Met Val Cys 20 25 30 cac cgg cct gag gga ctggag cag ctt gag gca cag acg aac ttc acc 623 His Arg Pro Glu Gly Leu GluGln Leu Glu Ala Gln Thr Asn Phe Thr 35 40 45 aag aga gaa ctg caa gtc ttgtac cgg gga ttc aaa aac gag tgc cct 671 Lys Arg Glu Leu Gln Val Leu TyrArg Gly Phe Lys Asn Glu Cys Pro 50 55 60 65 agc ggt gtg gtc aat gaa gaaaca ttc aag cag atc tac gct cag ttt 719 Ser Gly Val Val Asn Glu Glu ThrPhe Lys Gln Ile Tyr Ala Gln Phe 70 75 80 ttc cct cac gga gat gcc agc acatat gca cat tac ctc ttc aat gcc 767 Phe Pro His Gly Asp Ala Ser Thr TyrAla His Tyr Leu Phe Asn Ala 85 90 95 ttc gac acc acc cag aca ggc tct gtaaag ttc gag gac ttt gtg act 815 Phe Asp Thr Thr Gln Thr Gly Ser Val LysPhe Glu Asp Phe Val Thr 100 105 110 gct ctg tcg att tta ctg aga ggg acagtc cat gaa aaa cta agg tgg 863 Ala Leu Ser Ile Leu Leu Arg Gly Thr ValHis Glu Lys Leu Arg Trp 115 120 125 acg ttt aat ttg tat gac atc aat aaagac ggc tac ata aac aaa gag 911 Thr Phe Asn Leu Tyr Asp Ile Asn Lys AspGly Tyr Ile Asn Lys Glu 130 135 140 145 gag atg atg gac ata gtc aaa gccatc tat gac atg atg ggg aaa tac 959 Glu Met Met Asp Ile Val Lys Ala IleTyr Asp Met Met Gly Lys Tyr 150 155 160 acc tat cct gtg ctc aaa gag gacact ccc agg cag cat gtg gat gtc 1007 Thr Tyr Pro Val Leu Lys Glu Asp ThrPro Arg Gln His Val Asp Val 165 170 175 ttc ttc cag aaa atg gat aaa aataaa gat ggc att gta acg tta gat 1055 Phe Phe Gln Lys Met Asp Lys Asn LysAsp Gly Ile Val Thr Leu Asp 180 185 190 gaa ttt ctt gaa tca tgt cag gaggat gac aac atc atg aga tct cta 1103 Glu Phe Leu Glu Ser Cys Gln Glu AspAsp Asn Ile Met Arg Ser Leu 195 200 205 cag ctg ttc caa aat gtc atgtaactgagga cactggccat tctgctctca 1154 Gln Leu Phe Gln Asn Val Met 210215 gagacactga caaacacctt aatgccctga tctgcccttg ttccaatttt acacaccaac1214 tcttgggaca gaaatacctt ttacactttg gaagaattct ctgctgaaga ctttctacaa1274 aacctggcac cacgtggctc tgtctctgag ggacgagcgg agatccgact ttgttttgga1334 agcatgccca tctcttcatg ctgctgccct gtggaaggcc cctctgcttg agcttaatca1394 atagtgcaca gttttatgct tacacatatc cccaactcac tgcctccaag tcaggcagac1454 tctgatgaat ctgagccaaa tgtgcaccat cctccgatgg cctcccaagc caatgtgcct1514 gcttctcttc ctctggtggg aagaaagagt gttctacgga acaattagag cttaccatga1574 aaatattggg agaggcagca cctaacacat gtagaatagg actgaattat taagcatggt1634 gatatcagat gatgcaaatt gcccatgtca tttttttcaa aggtagggac aaatgattct1694 cccacactag cacctgtggt catagagcaa gtctcttaac atgcccagaa ggggaaccac1754 tgtccagtgg tctatccctc ctctccatcc cctgctcaaa cccagcactg catgtccctc1814 caagaaggtc cagaatgcct gcgaaacgct gtacttttat accctgttct aatcaataaa1874 cagaactatt tcgtaaaaaa aaaaaaaaaa aaa 1907 6 216 PRT Mus musculus 6Met Gly Ala Val Met Gly Thr Phe Ser Ser Leu Gln Thr Lys Gln Arg 1 5 1015 Arg Pro Ser Lys Asp Lys Ile Glu Asp Glu Leu Glu Met Thr Met Val 20 2530 Cys His Arg Pro Glu Gly Leu Glu Gln Leu Glu Ala Gln Thr Asn Phe 35 4045 Thr Lys Arg Glu Leu Gln Val Leu Tyr Arg Gly Phe Lys Asn Glu Cys 50 5560 Pro Ser Gly Val Val Asn Glu Glu Thr Phe Lys Gln Ile Tyr Ala Gln 65 7075 80 Phe Phe Pro His Gly Asp Ala Ser Thr Tyr Ala His Tyr Leu Phe Asn 8590 95 Ala Phe Asp Thr Thr Gln Thr Gly Ser Val Lys Phe Glu Asp Phe Val100 105 110 Thr Ala Leu Ser Ile Leu Leu Arg Gly Thr Val His Glu Lys LeuArg 115 120 125 Trp Thr Phe Asn Leu Tyr Asp Ile Asn Lys Asp Gly Tyr IleAsn Lys 130 135 140 Glu Glu Met Met Asp Ile Val Lys Ala Ile Tyr Asp MetMet Gly Lys 145 150 155 160 Tyr Thr Tyr Pro Val Leu Lys Glu Asp Thr ProArg Gln His Val Asp 165 170 175 Val Phe Phe Gln Lys Met Asp Lys Asn LysAsp Gly Ile Val Thr Leu 180 185 190 Asp Glu Phe Leu Glu Ser Cys Gln GluAsp Asp Asn Ile Met Arg Ser 195 200 205 Leu Gln Leu Phe Gln Asn Val Met210 215 7 1534 DNA Rattus sp. CDS (31)..(711) 7 gtcccaagtc gcacacaagtcttcgctgcc atg ggg gcc gtc atg ggt acc ttc 54 Met Gly Ala Val Met GlyThr Phe 1 5 tcg tcc ctg cag acc aaa caa agg cga ccc tct aaa gac atc gcctgg 102 Ser Ser Leu Gln Thr Lys Gln Arg Arg Pro Ser Lys Asp Ile Ala Trp10 15 20 tgg tat tac cag tat cag aga gac aag atc gag gat gat ctg gag atg150 Trp Tyr Tyr Gln Tyr Gln Arg Asp Lys Ile Glu Asp Asp Leu Glu Met 2530 35 40 acc atg gtt tgc cat cgg cct gag gga ctg gag cag ctt gag gca cag198 Thr Met Val Cys His Arg Pro Glu Gly Leu Glu Gln Leu Glu Ala Gln 4550 55 acg aac ttc acc aag aga gaa ctg caa gtc ctt tac cgg gga ttc aaa246 Thr Asn Phe Thr Lys Arg Glu Leu Gln Val Leu Tyr Arg Gly Phe Lys 6065 70 aac gag tgc ccc agt ggt gtg gtt aac gaa gag aca ttc aag cag atc294 Asn Glu Cys Pro Ser Gly Val Val Asn Glu Glu Thr Phe Lys Gln Ile 7580 85 tac gct cag ttt ttc cct cat gga gat gcc agc aca tac gca cat tac342 Tyr Ala Gln Phe Phe Pro His Gly Asp Ala Ser Thr Tyr Ala His Tyr 9095 100 ctc ttc aat gcc ttc gac acc acc cag aca ggc tct gta aag ttc gag390 Leu Phe Asn Ala Phe Asp Thr Thr Gln Thr Gly Ser Val Lys Phe Glu 105110 115 120 gac ttt gtg act gct ctg tcg att tta ctg aga gga acg gtc catgaa 438 Asp Phe Val Thr Ala Leu Ser Ile Leu Leu Arg Gly Thr Val His Glu125 130 135 aaa ctg agg tgg acg ttt aat ttg tac gac atc aat aaa gac ggctac 486 Lys Leu Arg Trp Thr Phe Asn Leu Tyr Asp Ile Asn Lys Asp Gly Tyr140 145 150 ata aac aaa gag gag atg atg gac ata gtg aaa gcc atc tat gacatg 534 Ile Asn Lys Glu Glu Met Met Asp Ile Val Lys Ala Ile Tyr Asp Met155 160 165 atg ggg aaa tac acc tat cct gtg ctc aaa gag gac act ccc aggcag 582 Met Gly Lys Tyr Thr Tyr Pro Val Leu Lys Glu Asp Thr Pro Arg Gln170 175 180 cac gtg gac gtc ttc ttc cag aaa atg gat aaa aat aaa gat ggcatt 630 His Val Asp Val Phe Phe Gln Lys Met Asp Lys Asn Lys Asp Gly Ile185 190 195 200 gta acg tta gac gaa ttt ctc gag tcc tgt cag gag gat gacaac atc 678 Val Thr Leu Asp Glu Phe Leu Glu Ser Cys Gln Glu Asp Asp AsnIle 205 210 215 atg agg tct cta cag ctg ttc caa aat gtc atg taactgaggacactggccat 731 Met Arg Ser Leu Gln Leu Phe Gln Asn Val Met 220 225cctgctctca gagacactga caaacacctc aatgccctga tctgcccttg ttccagtttt 791acacatcaac tctcgggaca gaaatacctt ttacactttg gaagaattct ctgctgaaga 851ctttctacaa aacctggcac cgcgtggctc agtctctgat tgccaactct tcctccctcc 911tcctcttgag agggacgagc tgaaatccga agtttgtttt ggaagcatgc ccatctctcc 971atgctgctgc tgccctgtgg aaggcccctc tgcttgagct taaacagtag tgcacagttt 1031tctgcgtata cagatcccca actcactgcc tctaagtcag gcagaccctg atcaatctga 1091accaaatgtg caccatcctc cgatggcctc ccaagccaat gtgcctgctt ctcttcctct 1151ggtgggaaga aagaacgctc tacagagcac ttagagctta ccatgaaaat actgggagag 1211gcagcaccta acacatgtag aataggactg aattattaag catggtggta tcagatgatg 1271caaacagccc atgtcatttt ttttccagag gtagggacta ataattctcc cacactagca 1331cctacgatca tagaacaagt cttttaacac atccaggagg gaaaccgctg cccagtggtc 1391tatcccttct ctccatcccc tgctcaagcc cagcactgca tgtctctccc ggaaggtcca 1451gaatgcctgt gaaatgctgt aacttttata ccctgttata atcaataaac agaactattt 1511cgtacaaaaa aaaaaaaaaa aaa 1534 8 227 PRT Rattus sp. 8 Met Gly Ala ValMet Gly Thr Phe Ser Ser Leu Gln Thr Lys Gln Arg 1 5 10 15 Arg Pro SerLys Asp Ile Ala Trp Trp Tyr Tyr Gln Tyr Gln Arg Asp 20 25 30 Lys Ile GluAsp Asp Leu Glu Met Thr Met Val Cys His Arg Pro Glu 35 40 45 Gly Leu GluGln Leu Glu Ala Gln Thr Asn Phe Thr Lys Arg Glu Leu 50 55 60 Gln Val LeuTyr Arg Gly Phe Lys Asn Glu Cys Pro Ser Gly Val Val 65 70 75 80 Asn GluGlu Thr Phe Lys Gln Ile Tyr Ala Gln Phe Phe Pro His Gly 85 90 95 Asp AlaSer Thr Tyr Ala His Tyr Leu Phe Asn Ala Phe Asp Thr Thr 100 105 110 GlnThr Gly Ser Val Lys Phe Glu Asp Phe Val Thr Ala Leu Ser Ile 115 120 125Leu Leu Arg Gly Thr Val His Glu Lys Leu Arg Trp Thr Phe Asn Leu 130 135140 Tyr Asp Ile Asn Lys Asp Gly Tyr Ile Asn Lys Glu Glu Met Met Asp 145150 155 160 Ile Val Lys Ala Ile Tyr Asp Met Met Gly Lys Tyr Thr Tyr ProVal 165 170 175 Leu Lys Glu Asp Thr Pro Arg Gln His Val Asp Val Phe PheGln Lys 180 185 190 Met Asp Lys Asn Lys Asp Gly Ile Val Thr Leu Asp GluPhe Leu Glu 195 200 205 Ser Cys Gln Glu Asp Asp Asn Ile Met Arg Ser LeuGln Leu Phe Gln 210 215 220 Asn Val Met 225 9 1540 DNA Mus musculus CDS(77)..(757) 9 atccacaccg atttcttttc aggggaggga agagacaggg cctggggtcccaagacgcac 60 acaagtcttc gctgcc atg ggg gcc gtc atg ggc act ttc tcc tccctg cag 112 Met Gly Ala Val Met Gly Thr Phe Ser Ser Leu Gln 1 5 10 accaaa caa agg cga ccc tct aaa gac atc gcc tgg tgg tat tac cag 160 Thr LysGln Arg Arg Pro Ser Lys Asp Ile Ala Trp Trp Tyr Tyr Gln 15 20 25 tat cagaga gac aag att gag gat gag cta gag atg acc atg gtt tgc 208 Tyr Gln ArgAsp Lys Ile Glu Asp Glu Leu Glu Met Thr Met Val Cys 30 35 40 cac cgg cctgag gga ctg gag cag ctt gag gca cag acg aac ttc acc 256 His Arg Pro GluGly Leu Glu Gln Leu Glu Ala Gln Thr Asn Phe Thr 45 50 55 60 aag aga gaactg caa gtc ttg tac cgg gga ttc aaa aac gag tgc cct 304 Lys Arg Glu LeuGln Val Leu Tyr Arg Gly Phe Lys Asn Glu Cys Pro 65 70 75 agc ggt gtg gtcaat gaa gaa aca ttc aag cag atc tac gct cag ttt 352 Ser Gly Val Val AsnGlu Glu Thr Phe Lys Gln Ile Tyr Ala Gln Phe 80 85 90 ttc cct cac gga gatgcc agc aca tat gca cat tac ctc ttc aat gcc 400 Phe Pro His Gly Asp AlaSer Thr Tyr Ala His Tyr Leu Phe Asn Ala 95 100 105 ttc gac acc acc cagaca ggc tct gta aag ttc gag gac ttt gtg act 448 Phe Asp Thr Thr Gln ThrGly Ser Val Lys Phe Glu Asp Phe Val Thr 110 115 120 gct ctg tcg att ttactg aga ggg aca gtc cat gaa aaa cta agg tgg 496 Ala Leu Ser Ile Leu LeuArg Gly Thr Val His Glu Lys Leu Arg Trp 125 130 135 140 acg ttt aat ttgtat gac atc aat aaa gac ggc tac ata aac aaa gag 544 Thr Phe Asn Leu TyrAsp Ile Asn Lys Asp Gly Tyr Ile Asn Lys Glu 145 150 155 gag atg atg gacata gtc aaa gcc atc tat gac atg atg ggg aaa tac 592 Glu Met Met Asp IleVal Lys Ala Ile Tyr Asp Met Met Gly Lys Tyr 160 165 170 acc tat cct gtgctc aaa gag gac act ccc agg cag cat gtg gat gtc 640 Thr Tyr Pro Val LeuLys Glu Asp Thr Pro Arg Gln His Val Asp Val 175 180 185 ttc ttc cag aaaatg gat aaa aat aaa gat ggc att gta acg tta gat 688 Phe Phe Gln Lys MetAsp Lys Asn Lys Asp Gly Ile Val Thr Leu Asp 190 195 200 gaa ttt ctt gaatca tgt cag gag gat gac aac atc atg aga tct cta 736 Glu Phe Leu Glu SerCys Gln Glu Asp Asp Asn Ile Met Arg Ser Leu 205 210 215 220 cag ctg ttccaa aat gtc atg taactgagga cactggccat tctgctctca 787 Gln Leu Phe Gln AsnVal Met 225 gagacactga caaacacctt aatgccctga tctgcccttg ttccaattttacacaccaac 847 tcttgggaca gaaatacctt ttacactttg gaagaattct ctgctgaagactttctacaa 907 aacctggcac cacgtggctc tgtctctgag ggacgagcgg agatccgactttgttttgga 967 agcatgccca tctcttcatg ctgctgccct gtggaaggcc cctctgcttgagcttaatca 1027 atagtgcaca gttttatgct tacacatatc cccaactcac tgcctccaagtcaggcagac 1087 tctgatgaat ctgagccaaa tgtgcaccat cctccgatgg cctcccaagccaatgtgcct 1147 gcttctcttc ctctggtggg aagaaagagt gttctacgga acaattagagcttaccatga 1207 aaatattggg agaggcagca cctaacacat gtagaatagg actgaattattaagcatggt 1267 gatatcagat gatgcaaatt gcccatgtca tttttttcaa aggtagggacaaatgattct 1327 cccacactag cacctgtggt catagagcaa gtctcttaac atgcccagaaggggaaccac 1387 tgtccagtgg tctatccctc ctctccatcc cctgctcaaa cccagcactgcatgtccctc 1447 caagaaggtc cagaatgcct gcgaaacgct gtacttttat accctgttctaatcaataaa 1507 cagaactatt tcgtacaaaa aaaaaaaaaa aaa 1540 10 227 PRT Musmusculus 10 Met Gly Ala Val Met Gly Thr Phe Ser Ser Leu Gln Thr Lys GlnArg 1 5 10 15 Arg Pro Ser Lys Asp Ile Ala Trp Trp Tyr Tyr Gln Tyr GlnArg Asp 20 25 30 Lys Ile Glu Asp Glu Leu Glu Met Thr Met Val Cys His ArgPro Glu 35 40 45 Gly Leu Glu Gln Leu Glu Ala Gln Thr Asn Phe Thr Lys ArgGlu Leu 50 55 60 Gln Val Leu Tyr Arg Gly Phe Lys Asn Glu Cys Pro Ser GlyVal Val 65 70 75 80 Asn Glu Glu Thr Phe Lys Gln Ile Tyr Ala Gln Phe PhePro His Gly 85 90 95 Asp Ala Ser Thr Tyr Ala His Tyr Leu Phe Asn Ala PheAsp Thr Thr 100 105 110 Gln Thr Gly Ser Val Lys Phe Glu Asp Phe Val ThrAla Leu Ser Ile 115 120 125 Leu Leu Arg Gly Thr Val His Glu Lys Leu ArgTrp Thr Phe Asn Leu 130 135 140 Tyr Asp Ile Asn Lys Asp Gly Tyr Ile AsnLys Glu Glu Met Met Asp 145 150 155 160 Ile Val Lys Ala Ile Tyr Asp MetMet Gly Lys Tyr Thr Tyr Pro Val 165 170 175 Leu Lys Glu Asp Thr Pro ArgGln His Val Asp Val Phe Phe Gln Lys 180 185 190 Met Asp Lys Asn Lys AspGly Ile Val Thr Leu Asp Glu Phe Leu Glu 195 200 205 Ser Cys Gln Glu AspAsp Asn Ile Met Arg Ser Leu Gln Leu Phe Gln 210 215 220 Asn Val Met 22511 955 DNA Rattus sp. CDS (345)..(953) Xaa at position 92 of thecorresponding amino acid sequence may be any amino acid 11 gtccgggcacacaacccctg gattcttcgg agaatatgcc gtgacggtgt tgccaattat 60 tagttctcttggctagcaga tgtttaggga ctggttaagc ctttggagaa attaccttag 120 gaaaacggggaaataaaagc aaagattacc atgaattgca agattaccta gcaattgcaa 180 ggtaggaggagagaggtgga gggcggagta gacaggaggg agggagaaag tgagaggaag 240 ctaggctggtggaaataacc ctgcacttgg aacagcggca aagaagcgcg attttccagc 300 tttaaatgcctgcccgcgtt ctgcttgcct acccgggaac ggag atg ttg acc cag 356 Met Leu ThrGln 1 ggc gag tct gaa ggg ctc cag acc ttg ggg ata gta gtg gtc ctg tgt404 Gly Glu Ser Glu Gly Leu Gln Thr Leu Gly Ile Val Val Val Leu Cys 5 1015 20 tcc tct ctg aaa cta ctg cac tac ctc ggg ctg att gac ttg tcg gat452 Ser Ser Leu Lys Leu Leu His Tyr Leu Gly Leu Ile Asp Leu Ser Asp 2530 35 gac aag atc gag gat gat ctg gag atg acc atg gtt tgc cat cgg cct500 Asp Lys Ile Glu Asp Asp Leu Glu Met Thr Met Val Cys His Arg Pro 4045 50 gag gga ctg gag cag ctt gag gca cag acg aac ttc acc aag aga gaa548 Glu Gly Leu Glu Gln Leu Glu Ala Gln Thr Asn Phe Thr Lys Arg Glu 5560 65 ctg caa gtc ctt tac cgg gga ttc aaa aac gag tgc ccc agt ggt gtg596 Leu Gln Val Leu Tyr Arg Gly Phe Lys Asn Glu Cys Pro Ser Gly Val 7075 80 gtt aac gaa gag aca ttc aag cng atc tac gct cag ttt ttc cct cat644 Val Asn Glu Glu Thr Phe Lys Xaa Ile Tyr Ala Gln Phe Phe Pro His 8590 95 100 gga gat gcc agc aca tac gca cat tac ctc ttc aat gcc ttc gacacc 692 Gly Asp Ala Ser Thr Tyr Ala His Tyr Leu Phe Asn Ala Phe Asp Thr105 110 115 acc cag aca ggc tct gta aag ttc gag gac ttt gtg act gct ctgtcg 740 Thr Gln Thr Gly Ser Val Lys Phe Glu Asp Phe Val Thr Ala Leu Ser120 125 130 att tta ctg aga gga acg gtc cat gaa aaa ctg aag tgg acg tttaat 788 Ile Leu Leu Arg Gly Thr Val His Glu Lys Leu Lys Trp Thr Phe Asn135 140 145 ttg tac gac atc aat aaa gac ggc tac ata aac aaa gag gag atgatg 836 Leu Tyr Asp Ile Asn Lys Asp Gly Tyr Ile Asn Lys Glu Glu Met Met150 155 160 gac ata gtg aaa gcc atc tat gac atg atg ggg aaa tac acc tatctt 884 Asp Ile Val Lys Ala Ile Tyr Asp Met Met Gly Lys Tyr Thr Tyr Leu165 170 175 180 gtg ctc aaa gag gac act tcc agg cag cac gtg gac gtc ttcttc cag 932 Val Leu Lys Glu Asp Thr Ser Arg Gln His Val Asp Val Phe PheGln 185 190 195 aaa atg gat aaa aat aaa gat gg 955 Lys Met Asp Lys AsnLys Asp 200 12 203 PRT Rattus sp. 12 Met Leu Thr Gln Gly Glu Ser Glu GlyLeu Gln Thr Leu Gly Ile Val 1 5 10 15 Val Val Leu Cys Ser Ser Leu LysLeu Leu His Tyr Leu Gly Leu Ile 20 25 30 Asp Leu Ser Asp Asp Lys Ile GluAsp Asp Leu Glu Met Thr Met Val 35 40 45 Cys His Arg Pro Glu Gly Leu GluGln Leu Glu Ala Gln Thr Asn Phe 50 55 60 Thr Lys Arg Glu Leu Gln Val LeuTyr Arg Gly Phe Lys Asn Glu Cys 65 70 75 80 Pro Ser Gly Val Val Asn GluGlu Thr Phe Lys Xaa Ile Tyr Ala Gln 85 90 95 Phe Phe Pro His Gly Asp AlaSer Thr Tyr Ala His Tyr Leu Phe Asn 100 105 110 Ala Phe Asp Thr Thr GlnThr Gly Ser Val Lys Phe Glu Asp Phe Val 115 120 125 Thr Ala Leu Ser IleLeu Leu Arg Gly Thr Val His Glu Lys Leu Lys 130 135 140 Trp Thr Phe AsnLeu Tyr Asp Ile Asn Lys Asp Gly Tyr Ile Asn Lys 145 150 155 160 Glu GluMet Met Asp Ile Val Lys Ala Ile Tyr Asp Met Met Gly Lys 165 170 175 TyrThr Tyr Leu Val Leu Lys Glu Asp Thr Ser Arg Gln His Val Asp 180 185 190Val Phe Phe Gln Lys Met Asp Lys Asn Lys Asp 195 200 13 2009 DNA Homosapiens CDS (207)..(1016) 13 ctcacctgct gcctagtgtt ccctctcctg ctccaggacctccgggtaga cctcagaccc 60 cgggcccatt cccagactca gcctcagccc ggacttccccagccccgaca gcacagtagg 120 ccgccagggg gcgccgtgtg agcgccctat cccggccacccggcgccccc tcccacggcc 180 cgggcgggag cggggcgccg ggggcc atg cgg ggc cagggc cgc aag gag agt 233 Met Arg Gly Gln Gly Arg Lys Glu Ser 1 5 ttg tccgat tcc cga gac ctg gac ggc tcc tac gac cag ctc acg ggc 281 Leu Ser AspSer Arg Asp Leu Asp Gly Ser Tyr Asp Gln Leu Thr Gly 10 15 20 25 cac cctcca ggg ccc act aaa aaa gcg ctg aag cag cga ttc ctc aag 329 His Pro ProGly Pro Thr Lys Lys Ala Leu Lys Gln Arg Phe Leu Lys 30 35 40 ctg ctg ccgtgc tgc ggg ccc caa gcc ctg ccc tca gtc agt gaa aca 377 Leu Leu Pro CysCys Gly Pro Gln Ala Leu Pro Ser Val Ser Glu Thr 45 50 55 tta gcc gcc ccagcc tcc ctc cgc ccc cac aga ccc cgc ctg ctg gac 425 Leu Ala Ala Pro AlaSer Leu Arg Pro His Arg Pro Arg Leu Leu Asp 60 65 70 cca gac agc gtg gacgat gaa ttt gaa ttg tcc acc gtg tgt cac cgg 473 Pro Asp Ser Val Asp AspGlu Phe Glu Leu Ser Thr Val Cys His Arg 75 80 85 cct gag ggt ctg gag cagctg cag gag caa acc aaa ttc acg cgc aag 521 Pro Glu Gly Leu Glu Gln LeuGln Glu Gln Thr Lys Phe Thr Arg Lys 90 95 100 105 gag ttg cag gtc ctgtac cgg ggc ttc aag aac gaa tgt ccc agc gga 569 Glu Leu Gln Val Leu TyrArg Gly Phe Lys Asn Glu Cys Pro Ser Gly 110 115 120 att gtc aat gag gagaac ttc aag cag att tac tcc cag ttc ttt cct 617 Ile Val Asn Glu Glu AsnPhe Lys Gln Ile Tyr Ser Gln Phe Phe Pro 125 130 135 caa gga gac tcc agcacc tat gcc act ttt ctc ttc aat gcc ttt gac 665 Gln Gly Asp Ser Ser ThrTyr Ala Thr Phe Leu Phe Asn Ala Phe Asp 140 145 150 acc aac cat gat ggctcg gtc agt ttt gag gac ttt gtg gct ggt ttg 713 Thr Asn His Asp Gly SerVal Ser Phe Glu Asp Phe Val Ala Gly Leu 155 160 165 tcc gtg att ctt cgggga act gta gat gac agg ctt aat tgg gcc ttc 761 Ser Val Ile Leu Arg GlyThr Val Asp Asp Arg Leu Asn Trp Ala Phe 170 175 180 185 aac ctg tat gacctt aac aag gac ggc tgc atc acc aag gag gaa atg 809 Asn Leu Tyr Asp LeuAsn Lys Asp Gly Cys Ile Thr Lys Glu Glu Met 190 195 200 ctt gac atc atgaag tcc atc tat gac atg atg ggc aag tac acg tac 857 Leu Asp Ile Met LysSer Ile Tyr Asp Met Met Gly Lys Tyr Thr Tyr 205 210 215 cct gca ctc cgggag gag gcc cca agg gaa cac gtg gag agc ttc ttc 905 Pro Ala Leu Arg GluGlu Ala Pro Arg Glu His Val Glu Ser Phe Phe 220 225 230 cag aag atg gacaga aac aag gat ggt gtg gtg acc att gag gaa ttc 953 Gln Lys Met Asp ArgAsn Lys Asp Gly Val Val Thr Ile Glu Glu Phe 235 240 245 att gag tct tgtcaa aag gat gag aac atc atg agg tcc atg cag ctc 1001 Ile Glu Ser Cys GlnLys Asp Glu Asn Ile Met Arg Ser Met Gln Leu 250 255 260 265 ttt gac aatgtc atc tagcccccag gagagggggt cagtgtttcc tggggggacc 1056 Phe Asp Asn ValIle 270 atgctctaac cctagtccag gcggacctca cccttctctt cccaggtctatcctcatcct 1116 acgcctccct gggggctgga gggatccaag agcttgggga ttcagtagtccagatctctg 1176 gagctgaagg ggccagagag tgggcagagt gcatctcggg gggtgttcccaactcccacc 1236 agctctcacc cccttcctgc ctgacaccca gtgttgagag tgcccctcctgtaggaattg 1296 agcggttccc cacctcctac cctactctag aaacacacta gagcgatgtctcctgctatg 1356 gtgcttcccc catccctgac ctcataaaca tttcccctaa gactcccctctcagagagaa 1416 tgctccattc ttggcactgg ctggcttctc agaccagcca ttgagagccctgtgggaggg 1476 ggacaagaat gtatagggag aaatcttggg cctgagtcaa tggataggtcctaggaggtg 1536 ggtggggttg agaatagaag ggcctggaca gattatgatt gctcaggcataccaggttat 1596 agctccaagt tccacaggtc tgctaccaca ggccatcaaa atataagtttccaggctttg 1656 cagaagacct tgtctcctta gaaatgcccc agaaattttc cacaccctcctcggtatcca 1716 tggagagcct ggggccagat atctggctca tctctggcat tgcttcctctccttccttcc 1776 tgcatgtgtt ggtggtggtt gtggtggggg aatgtggatg ggggatgtcctggctgatgc 1836 ctgccaaaat ttcatcccac cctccttgct tatcgtccct gttttgagggctatgacttg 1896 agtttttgtt tcccatgttc tctatagact tgggaccttc ctgaacttggggcctatcac 1956 tccccacagt ggatgcctta gaagggagag ggaaggaggg aggcaggcatagc 2009 14 270 PRT Homo sapiens 14 Met Arg Gly Gln Gly Arg Lys Glu SerLeu Ser Asp Ser Arg Asp Leu 1 5 10 15 Asp Gly Ser Tyr Asp Gln Leu ThrGly His Pro Pro Gly Pro Thr Lys 20 25 30 Lys Ala Leu Lys Gln Arg Phe LeuLys Leu Leu Pro Cys Cys Gly Pro 35 40 45 Gln Ala Leu Pro Ser Val Ser GluThr Leu Ala Ala Pro Ala Ser Leu 50 55 60 Arg Pro His Arg Pro Arg Leu LeuAsp Pro Asp Ser Val Asp Asp Glu 65 70 75 80 Phe Glu Leu Ser Thr Val CysHis Arg Pro Glu Gly Leu Glu Gln Leu 85 90 95 Gln Glu Gln Thr Lys Phe ThrArg Lys Glu Leu Gln Val Leu Tyr Arg 100 105 110 Gly Phe Lys Asn Glu CysPro Ser Gly Ile Val Asn Glu Glu Asn Phe 115 120 125 Lys Gln Ile Tyr SerGln Phe Phe Pro Gln Gly Asp Ser Ser Thr Tyr 130 135 140 Ala Thr Phe LeuPhe Asn Ala Phe Asp Thr Asn His Asp Gly Ser Val 145 150 155 160 Ser PheGlu Asp Phe Val Ala Gly Leu Ser Val Ile Leu Arg Gly Thr 165 170 175 ValAsp Asp Arg Leu Asn Trp Ala Phe Asn Leu Tyr Asp Leu Asn Lys 180 185 190Asp Gly Cys Ile Thr Lys Glu Glu Met Leu Asp Ile Met Lys Ser Ile 195 200205 Tyr Asp Met Met Gly Lys Tyr Thr Tyr Pro Ala Leu Arg Glu Glu Ala 210215 220 Pro Arg Glu His Val Glu Ser Phe Phe Gln Lys Met Asp Arg Asn Lys225 230 235 240 Asp Gly Val Val Thr Ile Glu Glu Phe Ile Glu Ser Cys GlnLys Asp 245 250 255 Glu Asn Ile Met Arg Ser Met Gln Leu Phe Asp Asn ValIle 260 265 270 15 1247 DNA Rattus sp. CDS (2)..(772) 15 c cga gat ctggac ggc tcc tat gac cag ctt acg ggc cac cct cca ggg 49 Arg Asp Leu AspGly Ser Tyr Asp Gln Leu Thr Gly His Pro Pro Gly 1 5 10 15 ccc agt aaaaaa gcc ctg aag cag cgt ttc ctc aag ctg ctg ccg tgc 97 Pro Ser Lys LysAla Leu Lys Gln Arg Phe Leu Lys Leu Leu Pro Cys 20 25 30 tgc ggg ccc caagcc ctg ccc tca gtc agt gaa aca tta gct gcc cca 145 Cys Gly Pro Gln AlaLeu Pro Ser Val Ser Glu Thr Leu Ala Ala Pro 35 40 45 gcc tcc ctc cgc ccccac aga ccc cgc ccg ctg gac cca gac agc gta 193 Ala Ser Leu Arg Pro HisArg Pro Arg Pro Leu Asp Pro Asp Ser Val 50 55 60 gag gat gag ttt gaa ttatcc acg gtg tgt cac cga cct gag ggc ctg 241 Glu Asp Glu Phe Glu Leu SerThr Val Cys His Arg Pro Glu Gly Leu 65 70 75 80 gaa caa ctc cag gaa cagacc aag ttc aca cgc aga gag ctg cag gtc 289 Glu Gln Leu Gln Glu Gln ThrLys Phe Thr Arg Arg Glu Leu Gln Val 85 90 95 ctg tac cga ggc ttc aag aacgaa tgc ccc agt ggg att gtc aac gag 337 Leu Tyr Arg Gly Phe Lys Asn GluCys Pro Ser Gly Ile Val Asn Glu 100 105 110 gag aac ttc aag cag att tattct cag ttc ttt ccc caa gga gac tcc 385 Glu Asn Phe Lys Gln Ile Tyr SerGln Phe Phe Pro Gln Gly Asp Ser 115 120 125 agc aac tat gct act ttt ctcttc aat gcc ttt gac acc aac cac gat 433 Ser Asn Tyr Ala Thr Phe Leu PheAsn Ala Phe Asp Thr Asn His Asp 130 135 140 ggc tct gtc agt ttt gag gacttt gtg gct ggt ttg tcg gtg att ctt 481 Gly Ser Val Ser Phe Glu Asp PheVal Ala Gly Leu Ser Val Ile Leu 145 150 155 160 cgg ggg acc ata gat gataga ctg agc tgg gct ttc aac tta tat gac 529 Arg Gly Thr Ile Asp Asp ArgLeu Ser Trp Ala Phe Asn Leu Tyr Asp 165 170 175 ctc aac aag gac ggc tgtatc aca aag gag gaa atg ctt gac att atg 577 Leu Asn Lys Asp Gly Cys IleThr Lys Glu Glu Met Leu Asp Ile Met 180 185 190 aag tcc atc tat gac atgatg ggc aag tac aca tac cct gcc ctc cgg 625 Lys Ser Ile Tyr Asp Met MetGly Lys Tyr Thr Tyr Pro Ala Leu Arg 195 200 205 gag gag gcc cca aga gaacac gtg gag agc ttc ttc cag aag atg gac 673 Glu Glu Ala Pro Arg Glu HisVal Glu Ser Phe Phe Gln Lys Met Asp 210 215 220 agg aac aag gac ggc gtggtg acc atc gag gaa ttc atc gag tct tgt 721 Arg Asn Lys Asp Gly Val ValThr Ile Glu Glu Phe Ile Glu Ser Cys 225 230 235 240 caa cag gac gag aacatc atg agg tcc atg cag ctc ttt gat aat gtc 769 Gln Gln Asp Glu Asn IleMet Arg Ser Met Gln Leu Phe Asp Asn Val 245 250 255 atc tagctccccagggagagggg ttagtgtgtc ctagggtgac caggctgtag 822 Ile tcctagtccagacgaaccta accctctctc tccaggcctg tcctcatctt acctgtaccc 882 tgggggctgtagggattcaa tatcctgggg cttcagtagt ccagatccct gagctaagtc 942 acaaaagtaggcaagagtag gcaagctaaa tctgggggct tcccaacccc cgacagctct 1002 caccccttctcaactgatac ctagtgctga ggacacccct ggtgtaggga ccaagtggtt 1062 ctccaccttctagtcccact ctagaaacca cattagacag aaggtctcct gctatggtgc 1122 tttccccatccctaatctct tagattttcc tcaagactcc cttctcagag aacacgctct 1182 gtccatgtccccagctgggg acatggacag agcgtgttct ctagttctag atcgcgagcg 1242 gccgc 124716 257 PRT Rattus sp. 16 Arg Asp Leu Asp Gly Ser Tyr Asp Gln Leu Thr GlyHis Pro Pro Gly 1 5 10 15 Pro Ser Lys Lys Ala Leu Lys Gln Arg Phe LeuLys Leu Leu Pro Cys 20 25 30 Cys Gly Pro Gln Ala Leu Pro Ser Val Ser GluThr Leu Ala Ala Pro 35 40 45 Ala Ser Leu Arg Pro His Arg Pro Arg Pro LeuAsp Pro Asp Ser Val 50 55 60 Glu Asp Glu Phe Glu Leu Ser Thr Val Cys HisArg Pro Glu Gly Leu 65 70 75 80 Glu Gln Leu Gln Glu Gln Thr Lys Phe ThrArg Arg Glu Leu Gln Val 85 90 95 Leu Tyr Arg Gly Phe Lys Asn Glu Cys ProSer Gly Ile Val Asn Glu 100 105 110 Glu Asn Phe Lys Gln Ile Tyr Ser GlnPhe Phe Pro Gln Gly Asp Ser 115 120 125 Ser Asn Tyr Ala Thr Phe Leu PheAsn Ala Phe Asp Thr Asn His Asp 130 135 140 Gly Ser Val Ser Phe Glu AspPhe Val Ala Gly Leu Ser Val Ile Leu 145 150 155 160 Arg Gly Thr Ile AspAsp Arg Leu Ser Trp Ala Phe Asn Leu Tyr Asp 165 170 175 Leu Asn Lys AspGly Cys Ile Thr Lys Glu Glu Met Leu Asp Ile Met 180 185 190 Lys Ser IleTyr Asp Met Met Gly Lys Tyr Thr Tyr Pro Ala Leu Arg 195 200 205 Glu GluAla Pro Arg Glu His Val Glu Ser Phe Phe Gln Lys Met Asp 210 215 220 ArgAsn Lys Asp Gly Val Val Thr Ile Glu Glu Phe Ile Glu Ser Cys 225 230 235240 Gln Gln Asp Glu Asn Ile Met Arg Ser Met Gln Leu Phe Asp Asn Val 245250 255 Ile 17 2343 DNA Mus musculus CDS (181)..(990) 17 cgggactctgaggtgggccc taaaatccag cgctccccag agaaaagcct tgccagcccc 60 tactcccggcccccagcccc agcaggtcgc tgcgccgcca gggggcactg tgtgagcgcc 120 ctatcctggccacccggcgc cccctcccac ggcccaggcg ggagcggggc gccgggggcc 180 atg cgg ggccaa ggc cga aag gag agt ttg tcc gaa tcc cga gat ttg 228 Met Arg Gly GlnGly Arg Lys Glu Ser Leu Ser Glu Ser Arg Asp Leu 1 5 10 15 gac ggc tcctat gac cag ctt acg ggc cac cct cca ggg ccc agt aaa 276 Asp Gly Ser TyrAsp Gln Leu Thr Gly His Pro Pro Gly Pro Ser Lys 20 25 30 aaa gcc ctg aagcag cgt ttc ctc aag ctg ctg ccg tgc tgc ggg ccc 324 Lys Ala Leu Lys GlnArg Phe Leu Lys Leu Leu Pro Cys Cys Gly Pro 35 40 45 caa gcc ctg ccc tcagtc agt gaa aca tta gct gcc cca gcc tcc ctc 372 Gln Ala Leu Pro Ser ValSer Glu Thr Leu Ala Ala Pro Ala Ser Leu 50 55 60 cgc ccc cac aga ccc cgcccg ctg gac cca gac agc gtg gag gat gag 420 Arg Pro His Arg Pro Arg ProLeu Asp Pro Asp Ser Val Glu Asp Glu 65 70 75 80 ttt gaa cta tcc acg gtgtgc cac cgg cct gag ggt ctg gaa caa ctc 468 Phe Glu Leu Ser Thr Val CysHis Arg Pro Glu Gly Leu Glu Gln Leu 85 90 95 cag gaa caa acc aag ttc acacgc aga gag ttg cag gtc ctg tac aga 516 Gln Glu Gln Thr Lys Phe Thr ArgArg Glu Leu Gln Val Leu Tyr Arg 100 105 110 ggc ttc aag aac gaa tgt cccagc gga att gtc aac gag gag aac ttc 564 Gly Phe Lys Asn Glu Cys Pro SerGly Ile Val Asn Glu Glu Asn Phe 115 120 125 aag caa att tat tct cag ttcttt ccc caa gga gac tcc agc aac tac 612 Lys Gln Ile Tyr Ser Gln Phe PhePro Gln Gly Asp Ser Ser Asn Tyr 130 135 140 gct act ttt ctc ttc aat gccttt gac acc aac cat gat ggc tct gtc 660 Ala Thr Phe Leu Phe Asn Ala PheAsp Thr Asn His Asp Gly Ser Val 145 150 155 160 agt ttt gag gac ttt gtggct ggt ttg tca gtg att ctt cgg gga acc 708 Ser Phe Glu Asp Phe Val AlaGly Leu Ser Val Ile Leu Arg Gly Thr 165 170 175 ata gat gat aga ctg aactgg gct ttc aac tta tat gac ctc aac aag 756 Ile Asp Asp Arg Leu Asn TrpAla Phe Asn Leu Tyr Asp Leu Asn Lys 180 185 190 gat ggc tgt atc acg aaggag gaa atg ctc gac atc atg aag tcc atc 804 Asp Gly Cys Ile Thr Lys GluGlu Met Leu Asp Ile Met Lys Ser Ile 195 200 205 tat gac atg atg ggc aagtac acc tac cct gcc ctc cgg gag gag gcc 852 Tyr Asp Met Met Gly Lys TyrThr Tyr Pro Ala Leu Arg Glu Glu Ala 210 215 220 ccg agg gaa cac gtg gagagc ttc ttc cag aag atg gac aga aac aag 900 Pro Arg Glu His Val Glu SerPhe Phe Gln Lys Met Asp Arg Asn Lys 225 230 235 240 gac ggc gtg gtg accatt gag gaa ttc att gag tct tgt caa cag gac 948 Asp Gly Val Val Thr IleGlu Glu Phe Ile Glu Ser Cys Gln Gln Asp 245 250 255 gag aac atc atg aggtcc atg caa ctc ttt gat aat gtc atc 990 Glu Asn Ile Met Arg Ser Met GlnLeu Phe Asp Asn Val Ile 260 265 270 tagctcccca gggagagggg ttagtgtgtcccagggtaac catgctgtag ccctagtcca 1050 ggcaaaccta accctcctct ccccgggtctgtcctcatcc tacctgtacc ctgggggctg 1110 tagggattca acatcctggc gcttcagtagtccagatccc tgagctaagt ggcgagagta 1170 ggcaagctaa gtctttggag ggtgggtgggggcgcgcaga ttcccaaccc ccgacgactc 1230 tcaccccttt ctcgactgat acccagtgctgaggctaccc ctggtgtcgg gaacgaccaa 1290 agtggttctc tgcctcccca gcccactctagagacccaca ctagacggga atatctcctg 1350 ctatggtgct ttccccatcc ctgaccgcagattttcctcc taagactccc ttctcagaga 1410 atatgctttt gtcccttgtc cctggctggcttttcagcct agcctttgag gaccctgtgg 1470 gaggggagaa taagaaagca gacaaaatcttggccctgag ccagtggtta ggtcctagga 1530 atcaggctgg agtggagacc agaaagcctgggcaggctat gagagcccca ggttggcttg 1590 tcaccgccag gttccacagg gctgctgctctgggtcagca gagtatgagt ttccagactt 1650 tccagaaggc cttatgtcct tagcaatgtcccagaaattc accatacact tctcagtgtc 1710 ttaggatcca gatgtccggt ccatccctgaaacctctccc tcctccttgc tcctatggtg 1770 ggagtggtgg ccaggggacg atgagtgagccggtgtcctg gatgatgcct gtcaaggtcc 1830 cacctaccct ccggctgtca agccgttctggtgaccctgt ttgattctcc atgacccctg 1890 tctagatgta gaggtgtgga gtgagtctagtggcagcctt aggggaatgg gaagaacgag 1950 aggggcactc catctgaacc cagtgtgggggcatccattc gaatctttgc ctggctcccc 2010 acaatgccct aggatcctct agggtccccacccccactct ttagtctacc cagagatgct 2070 ccagagctca cctagagggc agggaccataggatccaggt ccaacctgtc atcagcatcc 2130 ggccatgctg ctgctgctta ttaataaacctgcttgtcgt tcagcgcccc ttcccagtca 2190 gccagggtct gaggggaagg cccccactttcccgcctcct gtcagacatt gttgactgct 2250 ttgcattttg ggctcttcta cctatattttgtataataag aaagacacca gatccaataa 2310 aacacatggc tatgcacaaa aaaaaaaaaaaaa 2343 18 270 PRT Mus musculus 18 Met Arg Gly Gln Gly Arg Lys Glu SerLeu Ser Glu Ser Arg Asp Leu 1 5 10 15 Asp Gly Ser Tyr Asp Gln Leu ThrGly His Pro Pro Gly Pro Ser Lys 20 25 30 Lys Ala Leu Lys Gln Arg Phe LeuLys Leu Leu Pro Cys Cys Gly Pro 35 40 45 Gln Ala Leu Pro Ser Val Ser GluThr Leu Ala Ala Pro Ala Ser Leu 50 55 60 Arg Pro His Arg Pro Arg Pro LeuAsp Pro Asp Ser Val Glu Asp Glu 65 70 75 80 Phe Glu Leu Ser Thr Val CysHis Arg Pro Glu Gly Leu Glu Gln Leu 85 90 95 Gln Glu Gln Thr Lys Phe ThrArg Arg Glu Leu Gln Val Leu Tyr Arg 100 105 110 Gly Phe Lys Asn Glu CysPro Ser Gly Ile Val Asn Glu Glu Asn Phe 115 120 125 Lys Gln Ile Tyr SerGln Phe Phe Pro Gln Gly Asp Ser Ser Asn Tyr 130 135 140 Ala Thr Phe LeuPhe Asn Ala Phe Asp Thr Asn His Asp Gly Ser Val 145 150 155 160 Ser PheGlu Asp Phe Val Ala Gly Leu Ser Val Ile Leu Arg Gly Thr 165 170 175 IleAsp Asp Arg Leu Asn Trp Ala Phe Asn Leu Tyr Asp Leu Asn Lys 180 185 190Asp Gly Cys Ile Thr Lys Glu Glu Met Leu Asp Ile Met Lys Ser Ile 195 200205 Tyr Asp Met Met Gly Lys Tyr Thr Tyr Pro Ala Leu Arg Glu Glu Ala 210215 220 Pro Arg Glu His Val Glu Ser Phe Phe Gln Lys Met Asp Arg Asn Lys225 230 235 240 Asp Gly Val Val Thr Ile Glu Glu Phe Ile Glu Ser Cys GlnGln Asp 245 250 255 Glu Asn Ile Met Arg Ser Met Gln Leu Phe Asp Asn ValIle 260 265 270 19 1955 DNA Homo sapiens CDS (207)..(962) 19 ctcacctgctgcctagtgtt ccctctcctg ctccaggacc tccgggtaga cctcagaccc 60 cgggcccattcccagactca gcctcagccc ggacttcccc agccccgaca gcacagtagg 120 ccgccagggggcgccgtgtg agcgccctat cccggccacc cggcgccccc tcccacggcc 180 cgggcgggagcggggcgccg ggggcc atg cgg ggc cag ggc cgc aag gag agt 233 Met Arg GlyGln Gly Arg Lys Glu Ser 1 5 ttg tcc gat tcc cga gac ctg gac ggc tcc tacgac cag ctc acg ggc 281 Leu Ser Asp Ser Arg Asp Leu Asp Gly Ser Tyr AspGln Leu Thr Gly 10 15 20 25 cac cct cca ggg ccc act aaa aaa gcg ctg aagcag cga ttc ctc aag 329 His Pro Pro Gly Pro Thr Lys Lys Ala Leu Lys GlnArg Phe Leu Lys 30 35 40 ctg ctg ccg tgc tgc ggg ccc caa gcc ctg ccc tcagtc agt gaa aac 377 Leu Leu Pro Cys Cys Gly Pro Gln Ala Leu Pro Ser ValSer Glu Asn 45 50 55 agc gtg gac gat gaa ttt gaa ttg tcc acc gtg tgt caccgg cct gag 425 Ser Val Asp Asp Glu Phe Glu Leu Ser Thr Val Cys His ArgPro Glu 60 65 70 ggt ctg gag cag ctg cag gag caa acc aaa ttc acg cgc aaggag ttg 473 Gly Leu Glu Gln Leu Gln Glu Gln Thr Lys Phe Thr Arg Lys GluLeu 75 80 85 cag gtc ctg tac cgg ggc ttc aag aac gaa tgt ccc agc gga attgtc 521 Gln Val Leu Tyr Arg Gly Phe Lys Asn Glu Cys Pro Ser Gly Ile Val90 95 100 105 aat gag gag aac ttc aag cag att tac tcc cag ttc ttt cctcaa gga 569 Asn Glu Glu Asn Phe Lys Gln Ile Tyr Ser Gln Phe Phe Pro GlnGly 110 115 120 gac tcc agc acc tat gcc act ttt ctc ttc aat gcc ttt gacacc aac 617 Asp Ser Ser Thr Tyr Ala Thr Phe Leu Phe Asn Ala Phe Asp ThrAsn 125 130 135 cat gat ggc tcg gtc agt ttt gag gac ttt gtg gct ggt ttgtcc gtg 665 His Asp Gly Ser Val Ser Phe Glu Asp Phe Val Ala Gly Leu SerVal 140 145 150 att ctt cgg gga act gta gat gac agg ctt aat tgg gcc ttcaac ctg 713 Ile Leu Arg Gly Thr Val Asp Asp Arg Leu Asn Trp Ala Phe AsnLeu 155 160 165 tat gac ctt aac aag gac ggc tgc atc acc aag gag gaa atgctt gac 761 Tyr Asp Leu Asn Lys Asp Gly Cys Ile Thr Lys Glu Glu Met LeuAsp 170 175 180 185 atc atg aag tcc atc tat gac atg atg ggc aag tac acgtac cct gca 809 Ile Met Lys Ser Ile Tyr Asp Met Met Gly Lys Tyr Thr TyrPro Ala 190 195 200 ctc cgg gag gag gcc cca agg gaa cac gtg gag agc ttcttc cag aag 857 Leu Arg Glu Glu Ala Pro Arg Glu His Val Glu Ser Phe PheGln Lys 205 210 215 atg gac aga aac aag gat ggt gtg gtg acc att gag gaattc att gag 905 Met Asp Arg Asn Lys Asp Gly Val Val Thr Ile Glu Glu PheIle Glu 220 225 230 tct tgt caa aag gat gag aac atc atg agg tcc atg cagctc ttt gac 953 Ser Cys Gln Lys Asp Glu Asn Ile Met Arg Ser Met Gln LeuPhe Asp 235 240 245 aat gtc atc tagcccccag gagagggggt cagtgtttcctggggggacc 1002 Asn Val Ile 250 atgctctaac cctagtccag gcggacctcacccttctctt cccaggtcta tcctcatcct 1062 acgcctccct gggggctgga gggatccaagagcttgggga ttcagtagtc cagatctctg 1122 gagctgaagg ggccagagag tgggcagagtgcatctcggg gggtgttccc aactcccacc 1182 agctctcacc cccttcctgc ctgacacccagtgttgagag tgcccctcct gtaggaattg 1242 agcggttccc cacctcctac cctactctagaaacacacta gagcgatgtc tcctgctatg 1302 gtgcttcccc catccctgac ctcataaacatttcccctaa gactcccctc tcagagagaa 1362 tgctccattc ttggcactgg ctggcttctcagaccagcca ttgagagccc tgtgggaggg 1422 ggacaagaat gtatagggag aaatcttgggcctgagtcaa tggataggtc ctaggaggtg 1482 ggtggggttg agaatagaag ggcctggacagattatgatt gctcaggcat accaggttat 1542 agctccaagt tccacaggtc tgctaccacaggccatcaaa atataagttt ccaggctttg 1602 cagaagacct tgtctcctta gaaatgccccagaaattttc cacaccctcc tcggtatcca 1662 tggagagcct ggggccagat atctggctcatctctggcat tgcttcctct ccttccttcc 1722 tgcatgtgtt ggtggtggtt gtggtgggggaatgtggatg ggggatgtcc tggctgatgc 1782 ctgccaaaat ttcatcccac cctccttgcttatcgtccct gttttgaggg ctatgacttg 1842 agtttttgtt tcccatgttc tctatagacttgggaccttc ctgaacttgg ggcctatcac 1902 tccccacagt ggatgcctta gaagggagagggaaggaggg aggcaggcat agc 1955 20 252 PRT Homo sapiens 20 Met Arg GlyGln Gly Arg Lys Glu Ser Leu Ser Asp Ser Arg Asp Leu 1 5 10 15 Asp GlySer Tyr Asp Gln Leu Thr Gly His Pro Pro Gly Pro Thr Lys 20 25 30 Lys AlaLeu Lys Gln Arg Phe Leu Lys Leu Leu Pro Cys Cys Gly Pro 35 40 45 Gln AlaLeu Pro Ser Val Ser Glu Asn Ser Val Asp Asp Glu Phe Glu 50 55 60 Leu SerThr Val Cys His Arg Pro Glu Gly Leu Glu Gln Leu Gln Glu 65 70 75 80 GlnThr Lys Phe Thr Arg Lys Glu Leu Gln Val Leu Tyr Arg Gly Phe 85 90 95 LysAsn Glu Cys Pro Ser Gly Ile Val Asn Glu Glu Asn Phe Lys Gln 100 105 110Ile Tyr Ser Gln Phe Phe Pro Gln Gly Asp Ser Ser Thr Tyr Ala Thr 115 120125 Phe Leu Phe Asn Ala Phe Asp Thr Asn His Asp Gly Ser Val Ser Phe 130135 140 Glu Asp Phe Val Ala Gly Leu Ser Val Ile Leu Arg Gly Thr Val Asp145 150 155 160 Asp Arg Leu Asn Trp Ala Phe Asn Leu Tyr Asp Leu Asn LysAsp Gly 165 170 175 Cys Ile Thr Lys Glu Glu Met Leu Asp Ile Met Lys SerIle Tyr Asp 180 185 190 Met Met Gly Lys Tyr Thr Tyr Pro Ala Leu Arg GluGlu Ala Pro Arg 195 200 205 Glu His Val Glu Ser Phe Phe Gln Lys Met AspArg Asn Lys Asp Gly 210 215 220 Val Val Thr Ile Glu Glu Phe Ile Glu SerCys Gln Lys Asp Glu Asn 225 230 235 240 Ile Met Arg Ser Met Gln Leu PheAsp Asn Val Ile 245 250 21 2300 DNA Rattus sp. CDS (214)..(969) 21ctcacttgct gcccaaggct cctgctcctg ccccaggact ctgaggtggg ccctaaaacc 60cagcgctctc taaagaaaag ccttgccagc ccctactccc ggcccccaac cccagcaggt 120cgctgcgccg ccagggggcg ctgtgtgagc gccctattct ggccacccgg cgccccctcc 180cacggcccag gcgggagcgg ggcgccgggg gcc atg cgg ggc caa ggc aga aag 234 MetArg Gly Gln Gly Arg Lys 1 5 gag agt ttg tcc gaa tcc cga gat ctg gac ggctcc tat gac cag ctt 282 Glu Ser Leu Ser Glu Ser Arg Asp Leu Asp Gly SerTyr Asp Gln Leu 10 15 20 acg ggc cac cct cca ggg ccc agt aaa aaa gcc ctgaag cag cgt ttc 330 Thr Gly His Pro Pro Gly Pro Ser Lys Lys Ala Leu LysGln Arg Phe 25 30 35 ctc aag ctg ctg ccg tgc tgc ggg ccc caa gcc ctg ccctca gtc agt 378 Leu Lys Leu Leu Pro Cys Cys Gly Pro Gln Ala Leu Pro SerVal Ser 40 45 50 55 gaa aac agc gta gag gat gag ttt gaa tta tcc acg gtgtgt cac cga 426 Glu Asn Ser Val Glu Asp Glu Phe Glu Leu Ser Thr Val CysHis Arg 60 65 70 cct gag ggc ctg gaa caa ctc cag gaa cag acc aag ttc acacgc aga 474 Pro Glu Gly Leu Glu Gln Leu Gln Glu Gln Thr Lys Phe Thr ArgArg 75 80 85 gag ctg cag gtc ctg tac cga ggc ttc aag aac gaa tgc ccc agtggg 522 Glu Leu Gln Val Leu Tyr Arg Gly Phe Lys Asn Glu Cys Pro Ser Gly90 95 100 att gtc aac gag gag aac ttc aag cag att tat tct cag ttc tttccc 570 Ile Val Asn Glu Glu Asn Phe Lys Gln Ile Tyr Ser Gln Phe Phe Pro105 110 115 caa gga gac tcc agc aac tat gct act ttt ctc ttc aat gcc tttgac 618 Gln Gly Asp Ser Ser Asn Tyr Ala Thr Phe Leu Phe Asn Ala Phe Asp120 125 130 135 acc aac cac gat ggc tct gtc agt ttt gag gac ttt gtg gctggt ttg 666 Thr Asn His Asp Gly Ser Val Ser Phe Glu Asp Phe Val Ala GlyLeu 140 145 150 tcg gtg att ctt cgg ggg acc ata gat gat aga ctg agc tgggct ttc 714 Ser Val Ile Leu Arg Gly Thr Ile Asp Asp Arg Leu Ser Trp AlaPhe 155 160 165 aac tta tat gac ctc aac aag gac ggc tgt atc aca aag gaggaa atg 762 Asn Leu Tyr Asp Leu Asn Lys Asp Gly Cys Ile Thr Lys Glu GluMet 170 175 180 ctt gac att atg aag tcc atc tat gac atg atg ggc aag tacaca tac 810 Leu Asp Ile Met Lys Ser Ile Tyr Asp Met Met Gly Lys Tyr ThrTyr 185 190 195 cct gcc ctc cgg gag gag gcc cca aga gaa cac gtg gag agcttc ttc 858 Pro Ala Leu Arg Glu Glu Ala Pro Arg Glu His Val Glu Ser PhePhe 200 205 210 215 cag aag atg gac agg aac aag gac ggc gtg gtg acc atcgag gaa ttc 906 Gln Lys Met Asp Arg Asn Lys Asp Gly Val Val Thr Ile GluGlu Phe 220 225 230 atc gag tct tgt caa cag gac gag aac atc atg agg tccatg cag ctc 954 Ile Glu Ser Cys Gln Gln Asp Glu Asn Ile Met Arg Ser MetGln Leu 235 240 245 ttt gat aat gtc atc tagctcccca gggagagggg ttagtgtgtcctagggtgac 1009 Phe Asp Asn Val Ile 250 caggctgtag tcctagtcca gacgaacctaaccctctctc tccaggcctg tcctcatctt 1069 acctgtaccc tgggggctgt agggattcaatatcctgggg cttcagtagt ccagatccct 1129 gagctaagtc acaaaagtag gcaagagtaggcaagctaaa tctgggggct tcccaacccc 1189 cgacagctct caccccttct caactgatacctagtgctga ggacacccct ggtgtaggga 1249 ccaagtggtt ctccaccttc tagtcccactctagaaacca cattagacag aaggtctcct 1309 gctatggtgc tttccccatc cctaatctcttagattttcc tcaagactcc cttctcagag 1369 aacacgctct gtccatgtcc ccagctggcttctcagccta gcctttgagg gccctgtggg 1429 gaggcgggga caagaaagca gaaaagtcttggccccgagc cagtggttag gtcctaggaa 1489 ttggctggag tggaggccag aaagcctgggcagatgatga gagcccagct gggctgtcac 1549 tgcaggttcc ggggcctaca gccctgggtcagcagagtat gagttcccag actttccaga 1609 aggtccttag caatgtccca gaaattcaccgtacacttct cagtgtctta ggagggcccg 1669 ggatccagat gtctggttca tccctgaatcctctccctcc ttcttgctcg tatggtggga 1729 gtggtggcca ggggaagatg agtggtgtcccggatgatgc ctgtcaaggt cccacctccc 1789 ctccggctgt tctcatgaca gctgtttggttctccatgac ccctatctag atgtagaggc 1849 atggagtgag tcagggattt cccgaacttgagttttacca ctcctcctag tggctgcctt 1909 aggggaatgg gaagaaccca gtgtgggggcacccattaga atctttgccc ggctcctcac 1969 aatgccctag ggtcccctag ggtacccgctccctctgttt agtctaccca gagatgctcc 2029 tgagctcacc tagagggtag ggacggtaggctccaggtcc aacctctcca ggtcagcacc 2089 ctgccatgct gctgctcctc attaacaaacctgcttgtct cctcctgcgc cccttctcag 2149 tcagccaggg tctgagggga agggcctcccgtttccccat ccgtcagaca tggttgactg 2209 ctttgcattt tgggctcttc tatctattttgtaaaataag acatcagatc caataaaaca 2269 cacggctatg cacaaaaaaa aaaaaaaaaa a2300 22 252 PRT Rattus sp. 22 Met Arg Gly Gln Gly Arg Lys Glu Ser LeuSer Glu Ser Arg Asp Leu 1 5 10 15 Asp Gly Ser Tyr Asp Gln Leu Thr GlyHis Pro Pro Gly Pro Ser Lys 20 25 30 Lys Ala Leu Lys Gln Arg Phe Leu LysLeu Leu Pro Cys Cys Gly Pro 35 40 45 Gln Ala Leu Pro Ser Val Ser Glu AsnSer Val Glu Asp Glu Phe Glu 50 55 60 Leu Ser Thr Val Cys His Arg Pro GluGly Leu Glu Gln Leu Gln Glu 65 70 75 80 Gln Thr Lys Phe Thr Arg Arg GluLeu Gln Val Leu Tyr Arg Gly Phe 85 90 95 Lys Asn Glu Cys Pro Ser Gly IleVal Asn Glu Glu Asn Phe Lys Gln 100 105 110 Ile Tyr Ser Gln Phe Phe ProGln Gly Asp Ser Ser Asn Tyr Ala Thr 115 120 125 Phe Leu Phe Asn Ala PheAsp Thr Asn His Asp Gly Ser Val Ser Phe 130 135 140 Glu Asp Phe Val AlaGly Leu Ser Val Ile Leu Arg Gly Thr Ile Asp 145 150 155 160 Asp Arg LeuSer Trp Ala Phe Asn Leu Tyr Asp Leu Asn Lys Asp Gly 165 170 175 Cys IleThr Lys Glu Glu Met Leu Asp Ile Met Lys Ser Ile Tyr Asp 180 185 190 MetMet Gly Lys Tyr Thr Tyr Pro Ala Leu Arg Glu Glu Ala Pro Arg 195 200 205Glu His Val Glu Ser Phe Phe Gln Lys Met Asp Arg Asn Lys Asp Gly 210 215220 Val Val Thr Ile Glu Glu Phe Ile Glu Ser Cys Gln Gln Asp Glu Asn 225230 235 240 Ile Met Arg Ser Met Gln Leu Phe Asp Asn Val Ile 245 250 231859 DNA Homo sapiens CDS (207)..(866) 23 ctcacctgct gcctagtgttccctctcctg ctccaggacc tccgggtaga cctcagaccc 60 cgggcccatt cccagactcagcctcagccc ggacttcccc agccccgaca gcacagtagg 120 ccgccagggg gcgccgtgtgagcgccctat cccggccacc cggcgccccc tcccacggcc 180 cgggcgggag cggggcgccgggggcc atg cgg ggc cag ggc cgc aag gag agt 233 Met Arg Gly Gln Gly ArgLys Glu Ser 1 5 ttg tcc gat tcc cga gac ctg gac ggc tcc tac gac cag ctcacg gac 281 Leu Ser Asp Ser Arg Asp Leu Asp Gly Ser Tyr Asp Gln Leu ThrAsp 10 15 20 25 agc gtg gac gat gaa ttt gaa ttg tcc acc gtg tgt cac cggcct gag 329 Ser Val Asp Asp Glu Phe Glu Leu Ser Thr Val Cys His Arg ProGlu 30 35 40 ggt ctg gag cag ctg cag gag caa acc aaa ttc acg cgc aag gagttg 377 Gly Leu Glu Gln Leu Gln Glu Gln Thr Lys Phe Thr Arg Lys Glu Leu45 50 55 cag gtc ctg tac cgg ggc ttc aag aac gaa tgt ccc agc gga att gtc425 Gln Val Leu Tyr Arg Gly Phe Lys Asn Glu Cys Pro Ser Gly Ile Val 6065 70 aat gag gag aac ttc aag cag att tac tcc cag ttc ttt cct caa gga473 Asn Glu Glu Asn Phe Lys Gln Ile Tyr Ser Gln Phe Phe Pro Gln Gly 7580 85 gac tcc agc acc tat gcc act ttt ctc ttc aat gcc ttt gac acc aac521 Asp Ser Ser Thr Tyr Ala Thr Phe Leu Phe Asn Ala Phe Asp Thr Asn 9095 100 105 cat gat ggc tcg gtc agt ttt gag gac ttt gtg gct ggt ttg tccgtg 569 His Asp Gly Ser Val Ser Phe Glu Asp Phe Val Ala Gly Leu Ser Val110 115 120 att ctt cgg gga act gta gat gac agg ctt aat tgg gcc ttc aacctg 617 Ile Leu Arg Gly Thr Val Asp Asp Arg Leu Asn Trp Ala Phe Asn Leu125 130 135 tat gac ctt aac aag gac ggc tgc atc acc aag gag gaa atg cttgac 665 Tyr Asp Leu Asn Lys Asp Gly Cys Ile Thr Lys Glu Glu Met Leu Asp140 145 150 atc atg aag tcc atc tat gac atg atg ggc aag tac acg tac cctgca 713 Ile Met Lys Ser Ile Tyr Asp Met Met Gly Lys Tyr Thr Tyr Pro Ala155 160 165 ctc cgg gag gag gcc cca agg gaa cac gtg gag agc ttc ttc cagaag 761 Leu Arg Glu Glu Ala Pro Arg Glu His Val Glu Ser Phe Phe Gln Lys170 175 180 185 atg gac aga aac aag gat ggt gtg gtg acc att gag gaa ttcatt gag 809 Met Asp Arg Asn Lys Asp Gly Val Val Thr Ile Glu Glu Phe IleGlu 190 195 200 tct tgt caa aag gat gag aac atc atg agg tcc atg cag ctcttt gac 857 Ser Cys Gln Lys Asp Glu Asn Ile Met Arg Ser Met Gln Leu PheAsp 205 210 215 aat gtc atc tagcccccag gagagggggt cagtgtttcc tggggggacc906 Asn Val Ile 220 atgctctaac cctagtccag gcggacctca cccttctcttcccaggtcta tcctcatcct 966 acgcctccct gggggctgga gggatccaag agcttggggattcagtagtc cagatctctg 1026 gagctgaagg ggccagagag tgggcagagt gcatctcggggggtgttccc aactcccacc 1086 agctctcacc cccttcctgc ctgacaccca gtgttgagagtgcccctcct gtaggaattg 1146 agcggttccc cacctcctac cctactctag aaacacactagagcgatgtc tcctgctatg 1206 gtgcttcccc catccctgac ctcataaaca tttcccctaagactcccctc tcagagagaa 1266 tgctccattc ttggcactgg ctggcttctc agaccagccattgagagccc tgtgggaggg 1326 ggacaagaat gtatagggag aaatcttggg cctgagtcaatggataggtc ctaggaggtg 1386 ggtggggttg agaatagaag ggcctggaca gattatgattgctcaggcat accaggttat 1446 agctccaagt tccacaggtc tgctaccaca ggccatcaaaatataagttt ccaggctttg 1506 cagaagacct tgtctcctta gaaatgcccc agaaattttccacaccctcc tcggtatcca 1566 tggagagcct ggggccagat atctggctca tctctggcattgcttcctct ccttccttcc 1626 tgcatgtgtt ggtggtggtt gtggtggggg aatgtggatgggggatgtcc tggctgatgc 1686 ctgccaaaat ttcatcccac cctccttgct tatcgtccctgttttgaggg ctatgacttg 1746 agtttttgtt tcccatgttc tctatagact tgggaccttcctgaacttgg ggcctatcac 1806 tccccacagt ggatgcctta gaagggagag ggaaggagggaggcaggcat agc 1859 24 220 PRT Homo sapiens 24 Met Arg Gly Gln Gly ArgLys Glu Ser Leu Ser Asp Ser Arg Asp Leu 1 5 10 15 Asp Gly Ser Tyr AspGln Leu Thr Asp Ser Val Asp Asp Glu Phe Glu 20 25 30 Leu Ser Thr Val CysHis Arg Pro Glu Gly Leu Glu Gln Leu Gln Glu 35 40 45 Gln Thr Lys Phe ThrArg Lys Glu Leu Gln Val Leu Tyr Arg Gly Phe 50 55 60 Lys Asn Glu Cys ProSer Gly Ile Val Asn Glu Glu Asn Phe Lys Gln 65 70 75 80 Ile Tyr Ser GlnPhe Phe Pro Gln Gly Asp Ser Ser Thr Tyr Ala Thr 85 90 95 Phe Leu Phe AsnAla Phe Asp Thr Asn His Asp Gly Ser Val Ser Phe 100 105 110 Glu Asp PheVal Ala Gly Leu Ser Val Ile Leu Arg Gly Thr Val Asp 115 120 125 Asp ArgLeu Asn Trp Ala Phe Asn Leu Tyr Asp Leu Asn Lys Asp Gly 130 135 140 CysIle Thr Lys Glu Glu Met Leu Asp Ile Met Lys Ser Ile Tyr Asp 145 150 155160 Met Met Gly Lys Tyr Thr Tyr Pro Ala Leu Arg Glu Glu Ala Pro Arg 165170 175 Glu His Val Glu Ser Phe Phe Gln Lys Met Asp Arg Asn Lys Asp Gly180 185 190 Val Val Thr Ile Glu Glu Phe Ile Glu Ser Cys Gln Lys Asp GluAsn 195 200 205 Ile Met Arg Ser Met Gln Leu Phe Asp Asn Val Ile 210 215220 25 2191 DNA Simian sp. CDS (133)..(792) 25 cccacgcgtc cgcccacgcgtccgcggacg cgtggggtgc actaggccgc cagggggcgc 60 cgtgtgagcg ccctatcccggccacccggc gccccctccc acggaccggg cgggagcggg 120 gcgccggggg cc atg cggggc cag ggc cgc aag gag agt ttg tcc gat tcc 171 Met Arg Gly Gln Gly ArgLys Glu Ser Leu Ser Asp Ser 1 5 10 cga gac ctg gac gga tcc tac gac cagctc acg gac agc gtg gag gat 219 Arg Asp Leu Asp Gly Ser Tyr Asp Gln LeuThr Asp Ser Val Glu Asp 15 20 25 gaa ttt gaa ttg tcc acc gtg tgt cac cggcct gag ggt ctg gag cag 267 Glu Phe Glu Leu Ser Thr Val Cys His Arg ProGlu Gly Leu Glu Gln 30 35 40 45 ctg cag gag caa acc aaa ttc acg cgc aaggag ttg cag gtc ctg tac 315 Leu Gln Glu Gln Thr Lys Phe Thr Arg Lys GluLeu Gln Val Leu Tyr 50 55 60 cgg ggc ttc aag aac gaa tgt ccg agc gga attgtc aat gag gag aac 363 Arg Gly Phe Lys Asn Glu Cys Pro Ser Gly Ile ValAsn Glu Glu Asn 65 70 75 ttc aag caa att tac tcc cag ttc ttt cct caa ggagac tcc agc acc 411 Phe Lys Gln Ile Tyr Ser Gln Phe Phe Pro Gln Gly AspSer Ser Thr 80 85 90 tat gcc act ttt ctc ttc aat gcc ttt gac acc aac catgat ggc tcg 459 Tyr Ala Thr Phe Leu Phe Asn Ala Phe Asp Thr Asn His AspGly Ser 95 100 105 gtc agt ttt gag gac ttt gtg gct ggt ttg tcc gtg attctt cgg gga 507 Val Ser Phe Glu Asp Phe Val Ala Gly Leu Ser Val Ile LeuArg Gly 110 115 120 125 act gta gat gac agg ctt aat tgg gcc ttc aac ttgtat gac ctc aac 555 Thr Val Asp Asp Arg Leu Asn Trp Ala Phe Asn Leu TyrAsp Leu Asn 130 135 140 aag gac ggc tgc atc acc aag gag gaa atg ctt gacatc atg aag tcc 603 Lys Asp Gly Cys Ile Thr Lys Glu Glu Met Leu Asp IleMet Lys Ser 145 150 155 atc tat gac atg atg ggc aag tac aca tac cct gcactc cgg gag gag 651 Ile Tyr Asp Met Met Gly Lys Tyr Thr Tyr Pro Ala LeuArg Glu Glu 160 165 170 gcc cca agg gaa cat gtg gag aac ttc ttc cag aagatg gac aga aac 699 Ala Pro Arg Glu His Val Glu Asn Phe Phe Gln Lys MetAsp Arg Asn 175 180 185 aag gat ggc gtg gtg acc att gag gaa ttc att gagtct tgt caa aag 747 Lys Asp Gly Val Val Thr Ile Glu Glu Phe Ile Glu SerCys Gln Lys 190 195 200 205 gat gag aac atc atg agg tcc atg cag ctc tttgac aat gtc atc 792 Asp Glu Asn Ile Met Arg Ser Met Gln Leu Phe Asp AsnVal Ile 210 215 220 tagcccccag gagagggggt cagtgtttcc tggggggaccatgctctaac cctagtccag 852 gtggacctca cccttctctt cccaggtcta tccttgtcctaggcctccct gggggctgga 912 gggatccaag agcttgggga ttcagtagtc cagatctctggagctgaagg ggccagagag 972 tgggcagagt gcatcttggg gggtgttccc aactcccaccagctttcacc cgcttcctgc 1032 ctgacaccca gtgttgagag tgcccctcct gtaggaactgagtggttccc cacctcctac 1092 ccccactcta gaaacacact agacagatgt ctcctgctatggtgcttccc ccatccctga 1152 cttcataaac atttccccta aaactccctt ctcagagagaatgctccatt cttggcactg 1212 gctggcttct cagaccagcc tttgagagcc ctgtgggagggggacaagaa tgtatagggg 1272 agaaatcttg ggcctgagtc aatggatagg tcctaggaggtggctggggt tgagaataga 1332 aaggcctgga cacaatgtga ttgctcaggc ataccaagttatagctccaa gttccacagg 1392 tctgctacca caggccatca aaatataagt ttccaggctttgcagaagac cttgtctcct 1452 tggaaatgcc ccagatattt tccataccct cctcgatatccatggagagc ctggggctag 1512 atatctggca tatccctggc attgcttcct ctccttccttcctgcatgtg ttggtggtgg 1572 ttgtggcagg ggaatgtgga taggagatgt cctggcagatgcctgccaaa gtttcatccc 1632 accctccctg ctcatcgccc ctgttttgag ggctgtgacttgagtttttg tttcccatgt 1692 tctctataga cttgggacct tcctgaactt ggggcctatcactccccaca gtggatgcct 1752 tagaagggag agggaaggag ggaggcaggc atagcatctgaacccagtgt gggggcattc 1812 actaggatct tcaatcaacc cgggctctcc ccaaccccccagataacctc ctcagttccc 1872 tagagtctcc tcttgctcta ctcaatctac ccagagatgccccttagcac actcagaggg 1932 cagggaccat aggacccagg ttccaacccc attgtcagcaccccagccat gctgccatcc 1992 cttagcacac ctgctcgtcc cattcagctt accctcccagtcagccagaa tctgagggga 2052 gggcccccag agagccccct tccccatcag aagactgttgactgctttgc attttgggct 2112 cttctatata ttttgtaaaa taagaactat accagatctaataaaacaca atggctatgc 2172 aaaaaaaaaa aaaaaaaaa 2191 26 220 PRT Simiansp. 26 Met Arg Gly Gln Gly Arg Lys Glu Ser Leu Ser Asp Ser Arg Asp Leu 15 10 15 Asp Gly Ser Tyr Asp Gln Leu Thr Asp Ser Val Glu Asp Glu Phe Glu20 25 30 Leu Ser Thr Val Cys His Arg Pro Glu Gly Leu Glu Gln Leu Gln Glu35 40 45 Gln Thr Lys Phe Thr Arg Lys Glu Leu Gln Val Leu Tyr Arg Gly Phe50 55 60 Lys Asn Glu Cys Pro Ser Gly Ile Val Asn Glu Glu Asn Phe Lys Gln65 70 75 80 Ile Tyr Ser Gln Phe Phe Pro Gln Gly Asp Ser Ser Thr Tyr AlaThr 85 90 95 Phe Leu Phe Asn Ala Phe Asp Thr Asn His Asp Gly Ser Val SerPhe 100 105 110 Glu Asp Phe Val Ala Gly Leu Ser Val Ile Leu Arg Gly ThrVal Asp 115 120 125 Asp Arg Leu Asn Trp Ala Phe Asn Leu Tyr Asp Leu AsnLys Asp Gly 130 135 140 Cys Ile Thr Lys Glu Glu Met Leu Asp Ile Met LysSer Ile Tyr Asp 145 150 155 160 Met Met Gly Lys Tyr Thr Tyr Pro Ala LeuArg Glu Glu Ala Pro Arg 165 170 175 Glu His Val Glu Asn Phe Phe Gln LysMet Asp Arg Asn Lys Asp Gly 180 185 190 Val Val Thr Ile Glu Glu Phe IleGlu Ser Cys Gln Lys Asp Glu Asn 195 200 205 Ile Met Arg Ser Met Gln LeuPhe Asp Asn Val Ile 210 215 220 27 2057 DNA Simian sp. CDS (208)..(963)27 tgctgcccaa ggctcctgct cctgccccag gactctgagg tgggccctaa aacccagcgc 60tctctaaaga aaagccttgc cagcccctac tcccggcccc caaccccagc aggtcgctgc 120gccgccaggg ggcgctgtgt gagcgcccta ttctggccac ccggcgcccc ctcccacggc 180ccaggcggga gcggggcgcc gggggcc atg cgg ggc caa ggc aga aag gag agt 234Met Arg Gly Gln Gly Arg Lys Glu Ser 1 5 ttg tcc gaa tcc cga gat ctg gacggc tcc tat gac cag ctt acg ggc 282 Leu Ser Glu Ser Arg Asp Leu Asp GlySer Tyr Asp Gln Leu Thr Gly 10 15 20 25 cac cct cca ggg ccc agt aaa aaagcc ctg aag cag cgt ttc ctc aag 330 His Pro Pro Gly Pro Ser Lys Lys AlaLeu Lys Gln Arg Phe Leu Lys 30 35 40 ctg ctg ccg tgc tgc ggg ccc caa gccctg ccc tca gtc agt gaa aac 378 Leu Leu Pro Cys Cys Gly Pro Gln Ala LeuPro Ser Val Ser Glu Asn 45 50 55 agc gta gag gat gag ttt gaa tta tcc acggtg tgt cac cga cct gag 426 Ser Val Glu Asp Glu Phe Glu Leu Ser Thr ValCys His Arg Pro Glu 60 65 70 ggc ctg gaa caa ctc cag gaa cag acc aag ttcaca cgc aga gag ctg 474 Gly Leu Glu Gln Leu Gln Glu Gln Thr Lys Phe ThrArg Arg Glu Leu 75 80 85 cag gtc ctg tac cga ggc ttc aag aac gaa tgc cccagt ggg att gtc 522 Gln Val Leu Tyr Arg Gly Phe Lys Asn Glu Cys Pro SerGly Ile Val 90 95 100 105 aac gag gag aac ttc aag cag att tat tct cagttc ttt ccc caa gga 570 Asn Glu Glu Asn Phe Lys Gln Ile Tyr Ser Gln PhePhe Pro Gln Gly 110 115 120 gac tcc agc aac tat gct act ttt ctc ttc aatgcc ttt gac acc aac 618 Asp Ser Ser Asn Tyr Ala Thr Phe Leu Phe Asn AlaPhe Asp Thr Asn 125 130 135 cac gat ggc tct gtc agt ttt gag gac ttt gtggct ggt ttg tcg gtg 666 His Asp Gly Ser Val Ser Phe Glu Asp Phe Val AlaGly Leu Ser Val 140 145 150 att ctt cgg ggg acc ata gat gat aga ctg agctgg gct ttc aac tta 714 Ile Leu Arg Gly Thr Ile Asp Asp Arg Leu Ser TrpAla Phe Asn Leu 155 160 165 tat gac ctc aac aag gac ggc tgt atc aca aaggag gaa atg ctt gac 762 Tyr Asp Leu Asn Lys Asp Gly Cys Ile Thr Lys GluGlu Met Leu Asp 170 175 180 185 att atg aag tcc atc tat gac atg atg ggcaag tac aca tac cct gcc 810 Ile Met Lys Ser Ile Tyr Asp Met Met Gly LysTyr Thr Tyr Pro Ala 190 195 200 ctc cgg gag gag gcc cca aga gaa cac gtggag agc ttc ttc cag aag 858 Leu Arg Glu Glu Ala Pro Arg Glu His Val GluSer Phe Phe Gln Lys 205 210 215 atg gac agg aac aag gac ggc gtg gtg accatc gag gaa ttc atc gag 906 Met Asp Arg Asn Lys Asp Gly Val Val Thr IleGlu Glu Phe Ile Glu 220 225 230 tct tgt caa cag gac gag aac atc atg aggtcc atg cag ctc tca ccc 954 Ser Cys Gln Gln Asp Glu Asn Ile Met Arg SerMet Gln Leu Ser Pro 235 240 245 ctt ctc aac tgatacctag tgctgaggacacccctggtg tagggaccaa 1003 Leu Leu Asn 250 gtggttctcc accttctagtcccactctag aaaccacatt agacagaagg tctcctgcta 1063 tggtgctttc cccatccctaatctcttaga ttttcctcaa gactcccttc tcagagaaca 1123 cgctctgtcc atgtccccagctggcttctc agcctagcct ttgagggccc tgtggggagg 1183 cggggacaag aaagcagaaaagtcttggcc ccgagccagt ggttaggtcc taggaattgg 1243 ctggagtgga ggccagaaagcctgggcaga tgatgagagc ccagctgggc tgtcactgca 1303 ggttccgggg cctacagccctgggtcagca gagtatgagt tcccagactt tccagaaggt 1363 ccttagcaat gtcccagaaattcaccgtac acttctcagt gtcttaggag ggcccgggat 1423 ccagatgtct ggttcatccctgaatcctct ccctccttct tgctcgtatg gtgggagtgg 1483 tggccagggg aagatgagtggtgtcccgga tgatgcctgt caaggtccca cctcccctcc 1543 ggctgttctc atgacagctgtttggttctc catgacccct atctagatgt agaggcatgg 1603 agtgagtcag ggatttcccgaacttgagtt ttaccactcc tcctagtggc tgccttaggg 1663 gaatgggaag aacccagtgtgggggcaccc attagaatct ttgcccggct cctcacaatg 1723 ccctagggtc ccctagggtacccgctccct ctgtttagtc tacccagaga tgctcctgag 1783 ctcacctaga gggtagggacggtaggctcc aggtccaacc tctccaggtc agcaccctgc 1843 catgctgctg ctcctcattaacaaacctgc ttgtctcctc ctgcgcccct tctcagtcag 1903 ccagggtctg aggggaagggcctcccgttt ccccatccgt cagacatggt tgactgcttt 1963 gcattttggg ctcttctatctattttgtaa aataagacat cagatccaat aaaacacacg 2023 gctatgcaca aaaaaaaaaaaaaaaaaaaa aaaa 2057 28 252 PRT Simian sp. 28 Met Arg Gly Gln Gly ArgLys Glu Ser Leu Ser Glu Ser Arg Asp Leu 1 5 10 15 Asp Gly Ser Tyr AspGln Leu Thr Gly His Pro Pro Gly Pro Ser Lys 20 25 30 Lys Ala Leu Lys GlnArg Phe Leu Lys Leu Leu Pro Cys Cys Gly Pro 35 40 45 Gln Ala Leu Pro SerVal Ser Glu Asn Ser Val Glu Asp Glu Phe Glu 50 55 60 Leu Ser Thr Val CysHis Arg Pro Glu Gly Leu Glu Gln Leu Gln Glu 65 70 75 80 Gln Thr Lys PheThr Arg Arg Glu Leu Gln Val Leu Tyr Arg Gly Phe 85 90 95 Lys Asn Glu CysPro Ser Gly Ile Val Asn Glu Glu Asn Phe Lys Gln 100 105 110 Ile Tyr SerGln Phe Phe Pro Gln Gly Asp Ser Ser Asn Tyr Ala Thr 115 120 125 Phe LeuPhe Asn Ala Phe Asp Thr Asn His Asp Gly Ser Val Ser Phe 130 135 140 GluAsp Phe Val Ala Gly Leu Ser Val Ile Leu Arg Gly Thr Ile Asp 145 150 155160 Asp Arg Leu Ser Trp Ala Phe Asn Leu Tyr Asp Leu Asn Lys Asp Gly 165170 175 Cys Ile Thr Lys Glu Glu Met Leu Asp Ile Met Lys Ser Ile Tyr Asp180 185 190 Met Met Gly Lys Tyr Thr Tyr Pro Ala Leu Arg Glu Glu Ala ProArg 195 200 205 Glu His Val Glu Ser Phe Phe Gln Lys Met Asp Arg Asn LysAsp Gly 210 215 220 Val Val Thr Ile Glu Glu Phe Ile Glu Ser Cys Gln GlnAsp Glu Asn 225 230 235 240 Ile Met Arg Ser Met Gln Leu Ser Pro Leu LeuAsn 245 250 29 1904 DNA Rattus sp. CDS (1)..(675) 29 atg aac cac tgc cctcgc agg tgc cgg agc ccg ttg ggg cag gca gct 48 Met Asn His Cys Pro ArgArg Cys Arg Ser Pro Leu Gly Gln Ala Ala 1 5 10 15 cga tct ctc tac cagttg gta act ggg tcg ctg tcg cca gac agc gta 96 Arg Ser Leu Tyr Gln LeuVal Thr Gly Ser Leu Ser Pro Asp Ser Val 20 25 30 gag gat gag ttt gaa ttatcc acg gtg tgt cac cga cct gag ggc ctg 144 Glu Asp Glu Phe Glu Leu SerThr Val Cys His Arg Pro Glu Gly Leu 35 40 45 gaa caa ctc cag gaa cag accaag ttc aca cgc aga gag ctg cag gtc 192 Glu Gln Leu Gln Glu Gln Thr LysPhe Thr Arg Arg Glu Leu Gln Val 50 55 60 ctg tac cga ggc ttc aag aac gaatgc ccc agt ggg att gtc aac gag 240 Leu Tyr Arg Gly Phe Lys Asn Glu CysPro Ser Gly Ile Val Asn Glu 65 70 75 80 gag aac ttc aag cag att tat tctcag ttc ttt ccc caa gga gac tcc 288 Glu Asn Phe Lys Gln Ile Tyr Ser GlnPhe Phe Pro Gln Gly Asp Ser 85 90 95 agc aac tat gct act ttt ctc ttc aatgcc ttt gac acc aac cac gat 336 Ser Asn Tyr Ala Thr Phe Leu Phe Asn AlaPhe Asp Thr Asn His Asp 100 105 110 ggc tct gtc agt ttt gag gac ttt gtggct ggt ttg tcg gtg att ctt 384 Gly Ser Val Ser Phe Glu Asp Phe Val AlaGly Leu Ser Val Ile Leu 115 120 125 cgg ggg acc ata gat gat aga ctg agctgg gct ttc aac tta tat gac 432 Arg Gly Thr Ile Asp Asp Arg Leu Ser TrpAla Phe Asn Leu Tyr Asp 130 135 140 ctc aac aag gac ggc tgt atc aca aaggag gaa atg ctt gac att atg 480 Leu Asn Lys Asp Gly Cys Ile Thr Lys GluGlu Met Leu Asp Ile Met 145 150 155 160 aag tcc atc tat gac atg atg ggcaag tac aca tac cct gcc ctc cgg 528 Lys Ser Ile Tyr Asp Met Met Gly LysTyr Thr Tyr Pro Ala Leu Arg 165 170 175 gag gag gcc cca aga gaa cac gtggag agc ttc ttc cag aag atg gac 576 Glu Glu Ala Pro Arg Glu His Val GluSer Phe Phe Gln Lys Met Asp 180 185 190 agg aac aag gac ggc gtg gtg accatc gag gaa ttc atc gag tct tgt 624 Arg Asn Lys Asp Gly Val Val Thr IleGlu Glu Phe Ile Glu Ser Cys 195 200 205 caa cag gac gag aac atc atg aggtcc atg cag ctc ttt gat aat gtc 672 Gln Gln Asp Glu Asn Ile Met Arg SerMet Gln Leu Phe Asp Asn Val 210 215 220 atc tagctcccca gggagaggggttagtgtgtc ctagggtgac caggctgtag 725 Ile 225 tcctagtcca gacgaacctaaccctctctc tccaggcctg tcctcatctt acctgtaccc 785 tgggggctgt agggattcaatatcctgggg cttcagtagt ccagatccct gagctaagtc 845 acaaaagtag gcaagagtaggcaagctaaa tctgggggct tcccaacccc cgacagctct 905 caccccttct caactgatacctagtgctga ggacacccct ggtgtaggga ccaagtggtt 965 ctccaccttc tagtcccactctagaaacca cattagacag aaggtctcct gctatggtgc 1025 tttccccatc cctaatctcttagattttcc tcaagactcc cttctcagag aacacgctct 1085 gtccatgtcc ccagctggcttctcagccta gcctttgagg gccctgtggg gaggcgggga 1145 caagaaagca gaaaagtcttggccccgagc tagtggttag gtcctaggaa ttggctggag 1205 tggaggccag aaagcctgggcagatgatga gagcccagct gggctgtcac tgcaggttcc 1265 agggcctaca gccctgggtcagcagagtat gagttcccag actttccaga aggtccttag 1325 caatgtccca gaaattcaccatacacttct cagtgtcccg gatgatgcct gtcaaggtcc 1385 cacctcccct ccggctgttctcatgacagc tgtttggttc tccatgaccc ctatctagat 1445 gtagaggcat ggagtgagtcagggatttcc cgaacttgag ttttaccact cctcctagtg 1505 gctgccttag gggaatgggaagaacccagt gtgggggcac ccattagaat ctttgcccgg 1565 ttcctcacaa tgccctagggtcccctaggg tacccgctcc ctctgtttag tctacccaga 1625 gatgctcctg agctcacctagagggtaggg acggtaggct ccaggtccaa cctctccagg 1685 tcagcaccct gccatgctgctgctcctcat taacaaacct gcttgtctcc tcctgcgccc 1745 cttctcagtc agccagggtctgaggggaag ggcctcccgt ttccccatcc gtcagacatg 1805 gttgactgct ttgcattttgggctcttcta tctattttgt aaaataagac atcagatcca 1865 ataaaacaca cggctatgcacaaaaaaaaa aaaaaaaaa 1904 30 225 PRT Rattus sp. 30 Met Asn His Cys ProArg Arg Cys Arg Ser Pro Leu Gly Gln Ala Ala 1 5 10 15 Arg Ser Leu TyrGln Leu Val Thr Gly Ser Leu Ser Pro Asp Ser Val 20 25 30 Glu Asp Glu PheGlu Leu Ser Thr Val Cys His Arg Pro Glu Gly Leu 35 40 45 Glu Gln Leu GlnGlu Gln Thr Lys Phe Thr Arg Arg Glu Leu Gln Val 50 55 60 Leu Tyr Arg GlyPhe Lys Asn Glu Cys Pro Ser Gly Ile Val Asn Glu 65 70 75 80 Glu Asn PheLys Gln Ile Tyr Ser Gln Phe Phe Pro Gln Gly Asp Ser 85 90 95 Ser Asn TyrAla Thr Phe Leu Phe Asn Ala Phe Asp Thr Asn His Asp 100 105 110 Gly SerVal Ser Phe Glu Asp Phe Val Ala Gly Leu Ser Val Ile Leu 115 120 125 ArgGly Thr Ile Asp Asp Arg Leu Ser Trp Ala Phe Asn Leu Tyr Asp 130 135 140Leu Asn Lys Asp Gly Cys Ile Thr Lys Glu Glu Met Leu Asp Ile Met 145 150155 160 Lys Ser Ile Tyr Asp Met Met Gly Lys Tyr Thr Tyr Pro Ala Leu Arg165 170 175 Glu Glu Ala Pro Arg Glu His Val Glu Ser Phe Phe Gln Lys MetAsp 180 185 190 Arg Asn Lys Asp Gly Val Val Thr Ile Glu Glu Phe Ile GluSer Cys 195 200 205 Gln Gln Asp Glu Asn Ile Met Arg Ser Met Gln Leu PheAsp Asn Val 210 215 220 Ile 225 31 2841 DNA Homo sapiens CDS (1)..(768)31 atg cag ccg gct aag gaa gtg aca aag gcg tcg gac ggc agc ctc ctg 48Met Gln Pro Ala Lys Glu Val Thr Lys Ala Ser Asp Gly Ser Leu Leu 1 5 1015 ggg gac ctc ggg cac aca cca ctt agc aag aag gag ggt atc aag tgg 96Gly Asp Leu Gly His Thr Pro Leu Ser Lys Lys Glu Gly Ile Lys Trp 20 25 30cag agg ccg agg ctc agc cgc cag gct ttg atg aga tgc tgc ctg gtc 144 GlnArg Pro Arg Leu Ser Arg Gln Ala Leu Met Arg Cys Cys Leu Val 35 40 45 aagtgg atc ctg tcc agc aca gcc cca cag ggc tca gat agc agc gac 192 Lys TrpIle Leu Ser Ser Thr Ala Pro Gln Gly Ser Asp Ser Ser Asp 50 55 60 agt gagctg gag ctg tcc acg gtg cgc cac cag cca gag ggg ctg gac 240 Ser Glu LeuGlu Leu Ser Thr Val Arg His Gln Pro Glu Gly Leu Asp 65 70 75 80 cag ctgcag gcc cag acc aag ttc acc aag aag gag ctg cag tct ctc 288 Gln Leu GlnAla Gln Thr Lys Phe Thr Lys Lys Glu Leu Gln Ser Leu 85 90 95 tac agg ggcttt aag aat gag tgt ccc acg ggc ctg gtg gac gaa gac 336 Tyr Arg Gly PheLys Asn Glu Cys Pro Thr Gly Leu Val Asp Glu Asp 100 105 110 acc ttc aaactc att tac gcg cag ttc ttc cct cag gga gat gcc acc 384 Thr Phe Lys LeuIle Tyr Ala Gln Phe Phe Pro Gln Gly Asp Ala Thr 115 120 125 acc tat gcacac ttc ctc ttc aac gcc ttt gat gcg gac ggg aac ggg 432 Thr Tyr Ala HisPhe Leu Phe Asn Ala Phe Asp Ala Asp Gly Asn Gly 130 135 140 gcc atc cacttt gag gac ttt gtg gtt ggc ctc tcc atc ctg ctg cgg 480 Ala Ile His PheGlu Asp Phe Val Val Gly Leu Ser Ile Leu Leu Arg 145 150 155 160 ggc acagtc cac gag aag ctc aag tgg gcc ttt aat ctc tac gac att 528 Gly Thr ValHis Glu Lys Leu Lys Trp Ala Phe Asn Leu Tyr Asp Ile 165 170 175 aac aaggat ggc tac atc acc aaa gag gag atg ctg gcc atc atg aag 576 Asn Lys AspGly Tyr Ile Thr Lys Glu Glu Met Leu Ala Ile Met Lys 180 185 190 tcc atctat gac atg atg ggc cgc cac acc tac ccc atc ctg cgg gag 624 Ser Ile TyrAsp Met Met Gly Arg His Thr Tyr Pro Ile Leu Arg Glu 195 200 205 gac gcgccg gcg gag cac gtg gag agg ttc ttc gag aaa atg gac cgg 672 Asp Ala ProAla Glu His Val Glu Arg Phe Phe Glu Lys Met Asp Arg 210 215 220 aac caggat ggg gta gtg acc att gaa gag ttc ctg gag gcc tgt cag 720 Asn Gln AspGly Val Val Thr Ile Glu Glu Phe Leu Glu Ala Cys Gln 225 230 235 240 aaggat gag aac atc atg agc tcc atg cag ctg ttt gag aat gtc atc 768 Lys AspGlu Asn Ile Met Ser Ser Met Gln Leu Phe Glu Asn Val Ile 245 250 255taggacacgt ccaaaggagt gcatggccac agccacctcc acccccaaga aacctccatc 828ctgccaggag cagcctccaa gaaactttta aaaaatagat ttgcaaaaag tgaacagatt 888gctacacaca cacacacaca cacacacaca cacacacaca cacagccatt catctgggct 948ggcagagggg acagagttca gggaggggct gagtctggct aggggccgag tccaggagcc 1008ccagccagcc cttcccaggc cagcgaggcg aggctgcctc tgggtgagtg gctgacagag 1068caggtctgca ggccaccagc tgctggatgt caccaagaag gggctcgagt gcccctgcag 1128gggagggtcc aatctccggt gtgagcccac ctcgtcccgt tctccattct gctttcttgc 1188cacacagtgg gccggcccca ggctcccctg gtctcctccc cgtagccact ctctgcccac 1248tacctatgct tctagaaagc ccctcacctc aggaccccag agggaccagc tggggggcag 1308gggggagagg gggtaatgga ggccaagcct gcagctttct ggaaattctt ccctgggggt 1368cccaggatcc cctgctactc cactgacctg gaagagctgg gtaccaggcc acccactgtg 1428gggcaagcct gagtggtgag gggccactgg gccccattct ccctccatgg caggaaggcg 1488ggggatttca agtttaggga ttgggtcgtg gtggagaatc tgagggcact ctctgccagc 1548tccacagggt gggatgagcc tctccttgcc ccagtcctgg ttcagtggga atgcagtggg 1608tggggctgta cacaccctcc agcacagact gttccctcca aggtcctctt aggtcccggg 1668aggaacgtgg ttcagagact ggcagccagg gagcccgggg cagagctcag aggagtctgg 1728gaaggggcgt gtccctcctc ttcctgtagt gcccctccca tggcccagca gcttggctga 1788gccccctctc ctgaagcagt gtcgccgtcc ctctgccttg cacaaaaagc acaagcattc 1848cttagcagct caggcgcagc cctagtggga gcccagcaca ctgcttctcg gaggccaggc 1908cctcctgctg gctgaggctt gggcccagta gccccaatat ggtggccctg gggaagaggc 1968cttgggggtc tgctctgtgc ctgggatcag tggggcccca aagcccagcc cggctgacca 2028acattcaaaa gcacaaaccc tggggactct gcttggctgt cccctccatc tggggatgga 2088gaatgccagc ccaaagctgg agccaatggt gagggctgag agggctgtgg ctgggtggtc 2148agcagaaacc cccaggagga gagagatgct gctcccgcct gattggggcc tcacccagaa 2208ggaacccggt cccaggccgc atggcccctc caggaacatt cccacataat acattccatc 2268acagccagcc cagctccact cagggctggc ccggggagtc cccgtgtgcc ccaagaggct 2328agccccaggg tgagcagggc cctcagagga aaggcagtat ggcggaggcc atgggggccc 2388ctcggcattc acacacagcc tggcctcccc tgcggagctg catggacgcc tggctccagg 2448ctccaggctg actgggggcc tctgcctcca ggagggcatc agctttccct ggctcaggga 2508tcttctccct cccctcaccc gctgcccagc cctcccagct ggtgtcactc tgcctctaag 2568gccaaggcct caggagagca tcaccaccac acccctgccg gccttggcct tggggccaga 2628ctggctgcac agcccaacca ggaggggtct gcctcccacg ctgggacaca gaccggccgc 2688atgtctgcat ggcagaagcg tctcccttgg ccacggcctg ggagggtggt tcctgttctc 2748agcatccact aatattcagt cctgtatatt ttaataaaat aaacttgaca aaggaaaaaa 2808aaaaaaaaaa aattcctgcg gccgcgttct cca 2841 32 256 PRT Homo sapiens 32 MetGln Pro Ala Lys Glu Val Thr Lys Ala Ser Asp Gly Ser Leu Leu 1 5 10 15Gly Asp Leu Gly His Thr Pro Leu Ser Lys Lys Glu Gly Ile Lys Trp 20 25 30Gln Arg Pro Arg Leu Ser Arg Gln Ala Leu Met Arg Cys Cys Leu Val 35 40 45Lys Trp Ile Leu Ser Ser Thr Ala Pro Gln Gly Ser Asp Ser Ser Asp 50 55 60Ser Glu Leu Glu Leu Ser Thr Val Arg His Gln Pro Glu Gly Leu Asp 65 70 7580 Gln Leu Gln Ala Gln Thr Lys Phe Thr Lys Lys Glu Leu Gln Ser Leu 85 9095 Tyr Arg Gly Phe Lys Asn Glu Cys Pro Thr Gly Leu Val Asp Glu Asp 100105 110 Thr Phe Lys Leu Ile Tyr Ala Gln Phe Phe Pro Gln Gly Asp Ala Thr115 120 125 Thr Tyr Ala His Phe Leu Phe Asn Ala Phe Asp Ala Asp Gly AsnGly 130 135 140 Ala Ile His Phe Glu Asp Phe Val Val Gly Leu Ser Ile LeuLeu Arg 145 150 155 160 Gly Thr Val His Glu Lys Leu Lys Trp Ala Phe AsnLeu Tyr Asp Ile 165 170 175 Asn Lys Asp Gly Tyr Ile Thr Lys Glu Glu MetLeu Ala Ile Met Lys 180 185 190 Ser Ile Tyr Asp Met Met Gly Arg His ThrTyr Pro Ile Leu Arg Glu 195 200 205 Asp Ala Pro Ala Glu His Val Glu ArgPhe Phe Glu Lys Met Asp Arg 210 215 220 Asn Gln Asp Gly Val Val Thr IleGlu Glu Phe Leu Glu Ala Cys Gln 225 230 235 240 Lys Asp Glu Asn Ile MetSer Ser Met Gln Leu Phe Glu Asn Val Ile 245 250 255 33 442 DNA Rattussp. CDS (1)..(327) 33 ttt gag gac ttt gtg gtt ggg ctc tcc atc ctg cttcga ggg acc gtc 48 Phe Glu Asp Phe Val Val Gly Leu Ser Ile Leu Leu ArgGly Thr Val 1 5 10 15 cat gag aag ctc aag tgg gcc ttc aat ctc tac gacatc aac aag gac 96 His Glu Lys Leu Lys Trp Ala Phe Asn Leu Tyr Asp IleAsn Lys Asp 20 25 30 ggt tac atc acc aaa gag gag atg ctg gcc atc atg aagtcc atc tac 144 Gly Tyr Ile Thr Lys Glu Glu Met Leu Ala Ile Met Lys SerIle Tyr 35 40 45 gac atg atg ggc cgc cac acc tac cct atc ctg cgg gag gacgca cct 192 Asp Met Met Gly Arg His Thr Tyr Pro Ile Leu Arg Glu Asp AlaPro 50 55 60 ctg gag cat gtg gag agg ttc ttc cag aaa atg gac agg aac caggat 240 Leu Glu His Val Glu Arg Phe Phe Gln Lys Met Asp Arg Asn Gln Asp65 70 75 80 gga gta gtg act att gat gaa ttt ctg gag act tgt cag aag gacgag 288 Gly Val Val Thr Ile Asp Glu Phe Leu Glu Thr Cys Gln Lys Asp Glu85 90 95 aac atc atg agc tcc atg cag ctg ttt gag aac gtc atc taggacatgt337 Asn Ile Met Ser Ser Met Gln Leu Phe Glu Asn Val Ile 100 105aggaggggac cctgggtggc catgggttct caacccagag aagcctcaat cctgacagga 397gaagcctcta tgagaaacat ttttctaata tatttgcaaa aagtg 442 34 109 PRT Rattussp. 34 Phe Glu Asp Phe Val Val Gly Leu Ser Ile Leu Leu Arg Gly Thr Val 15 10 15 His Glu Lys Leu Lys Trp Ala Phe Asn Leu Tyr Asp Ile Asn Lys Asp20 25 30 Gly Tyr Ile Thr Lys Glu Glu Met Leu Ala Ile Met Lys Ser Ile Tyr35 40 45 Asp Met Met Gly Arg His Thr Tyr Pro Ile Leu Arg Glu Asp Ala Pro50 55 60 Leu Glu His Val Glu Arg Phe Phe Gln Lys Met Asp Arg Asn Gln Asp65 70 75 80 Gly Val Val Thr Ile Asp Glu Phe Leu Glu Thr Cys Gln Lys AspGlu 85 90 95 Asn Ile Met Ser Ser Met Gln Leu Phe Glu Asn Val Ile 100 10535 2644 DNA Mus musculus CDS (49)..(816) 35 cgggctgcaa agcgggaagattagtgacgg tccctttcag cagcagag atg cag agg 57 Met Gln Arg 1 acc aag gaagcc gtg aag gca tca gat ggc aac ctc ctg gga gat cct 105 Thr Lys Glu AlaVal Lys Ala Ser Asp Gly Asn Leu Leu Gly Asp Pro 5 10 15 ggg cgc ata ccactg agc aag agg gaa agc atc aag tgg caa agg cca 153 Gly Arg Ile Pro LeuSer Lys Arg Glu Ser Ile Lys Trp Gln Arg Pro 20 25 30 35 cgg ttc acc cgccag gcc ctg atg cgt tgc tgc tta atc aag tgg atc 201 Arg Phe Thr Arg GlnAla Leu Met Arg Cys Cys Leu Ile Lys Trp Ile 40 45 50 ctg tcc agt gct gcccca caa ggc tca gac agc agt gac agt gaa ctg 249 Leu Ser Ser Ala Ala ProGln Gly Ser Asp Ser Ser Asp Ser Glu Leu 55 60 65 gag tta tcc acg gtg cgccat cag cca gag ggc ttg gac cag cta caa 297 Glu Leu Ser Thr Val Arg HisGln Pro Glu Gly Leu Asp Gln Leu Gln 70 75 80 gct cag acc aag ttc acc aagaag gag ctg cag tcc ctt tac cga ggc 345 Ala Gln Thr Lys Phe Thr Lys LysGlu Leu Gln Ser Leu Tyr Arg Gly 85 90 95 ttc aag aat gag tgt ccc aca ggcctg gtg gat gaa gac acc ttc aaa 393 Phe Lys Asn Glu Cys Pro Thr Gly LeuVal Asp Glu Asp Thr Phe Lys 100 105 110 115 ctc att tat tcc cag ttc ttccct cag gga gat gcc acc acc tat gca 441 Leu Ile Tyr Ser Gln Phe Phe ProGln Gly Asp Ala Thr Thr Tyr Ala 120 125 130 cac ttc ctc ttc aat gcc tttgat gct gat ggg aac ggg gcc atc cac 489 His Phe Leu Phe Asn Ala Phe AspAla Asp Gly Asn Gly Ala Ile His 135 140 145 ttt gag gac ttt gtg gtt gggctc tcc atc ctg ctt cga ggg acg gtc 537 Phe Glu Asp Phe Val Val Gly LeuSer Ile Leu Leu Arg Gly Thr Val 150 155 160 cat gag aag ctc aag tgg gccttc aat ctc tat gac att aac aag gat 585 His Glu Lys Leu Lys Trp Ala PheAsn Leu Tyr Asp Ile Asn Lys Asp 165 170 175 ggt tgc atc acc aag gag gagatg ctg gcc atc atg aag tcc atc tac 633 Gly Cys Ile Thr Lys Glu Glu MetLeu Ala Ile Met Lys Ser Ile Tyr 180 185 190 195 gac atg atg ggc cgc cacacc tac ccc atc ctg cgg gag gat gca ccc 681 Asp Met Met Gly Arg His ThrTyr Pro Ile Leu Arg Glu Asp Ala Pro 200 205 210 ctg gag cat gtg gag aggttc ttt cag aaa atg gac agg aac cag gat 729 Leu Glu His Val Glu Arg PhePhe Gln Lys Met Asp Arg Asn Gln Asp 215 220 225 gga gtg gtg acc att gatgaa ttt ctg gag act tgt cag aag gat gag 777 Gly Val Val Thr Ile Asp GluPhe Leu Glu Thr Cys Gln Lys Asp Glu 230 235 240 aac atc atg aac tcc atgcag ctg ttt gag aac gtc atc taggacatgt 826 Asn Ile Met Asn Ser Met GlnLeu Phe Glu Asn Val Ile 245 250 255 gggaggggac cccagtggtc attgcttctcaacccagaga agcctcaatc ctgacaggag 886 aagcctctat gagaaacatt tttctaatatatttgcaaaa agtgagcagt ttacttccaa 946 gacacagcca ccgtcacaca cagacacagacatacagaca cacacacaca cacacacaca 1006 tggttcctct ggcttggcca aggaagtggcagccagaagg cacccccgcc tattcctagg 1066 tcaataaaaa aggctgcctc tgggatggccagccctggct agatgttacc cacaaggaac 1126 tcagagatcg agaggaccag gtctacaaagctaaggtccc tgtgtctttt ctaccactcg 1186 ggagatcaaa ctactccctg cctatggacccatgctctta ggaagctccc agaaactcca 1246 aggggacaaa gaggggagag gtctataggaagaaatggtt ttggaagctg ggcttgcagc 1306 cttatgctaa tgatcacctg gggtcctggaacccgagtgc caggctacct actatgccgt 1366 gagcttagat agtgaggggc cattggactaagacctcctg taagagtggg gcaggattga 1426 ggtttttgga gaaactgagg aaacaatttgtccataccac tgggtgaaga ctgctggcca 1486 gtgggaatgt ggctggtgga gatttcccaacttccagcac caggatggcc tctccaaggt 1546 cctctttgat tccctgggga gatcacctggctcatagact gacaaccagg gaactgggct 1606 gaaatgggag gtctggtagg gggcatccccctccttttcc ctggccactt gccacccagt 1666 tccttaacac agtggatcgg ccacacctctgtggctgccc ttgaacagac tcatcccgac 1726 caagacaaaa aagcacaaac tcctagcagctcaggccaag cccacaaggg aaggcctggg 1786 tccctgcagc cctgattcag tggccgaggaagacgctcag acatccatcc tgtacctcgg 1846 agccttgggg gtctcacagc cctttcccagcccagctcgc caacattcta aagcacaaac 1906 ctgcggattc tgcttgcttg ggctgcgccctggggattga aggccactgt taaccctaag 1966 ctggagctag ccctgagggc tggggacctgtgaccaggca acaggtcagc agaccctcag 2026 gaggagagag agctgttcct gcctccccaggcctcgccca gaaggaacag tgtcccaaga 2086 agcatgtttc ctggaggaac atccccacaaaagtacattc catcatctga agcccggtct 2146 ctgctcaggc ctgcctctga aagtccacgtgtgttcccca gaaggccagc cccaagataa 2206 gggaggtcct tagaggaagg acagggtgacaacaccccta tacacaggtg gaccccccct 2266 ctgaggactg tactgacccc atctccatcctgaccggggc cttcctttac ccgatctaca 2326 gaccaccagt tctccctggc tcagggaccccctgtccccc agtctgactc ttcccatcga 2386 ggtccctgtc ttgtgaaaag ccaaggccacgggaaaaggc caccactcta acctgctgca 2446 tcccttagcc tctggctgca cgcccaacctggaggggtct gtcccctttg cagggacaca 2506 gactggccgc atgtccgcat ggcagaagcgtctcccttgg gtgcagcctg gaagggtggt 2566 ttctgtctca gcgcccacca atattcagtcctatatattt taataaaaga aacttgacaa 2626 aggaaaaaaa aaaaaaaa 2644 36 256PRT Mus musculus 36 Met Gln Arg Thr Lys Glu Ala Val Lys Ala Ser Asp GlyAsn Leu Leu 1 5 10 15 Gly Asp Pro Gly Arg Ile Pro Leu Ser Lys Arg GluSer Ile Lys Trp 20 25 30 Gln Arg Pro Arg Phe Thr Arg Gln Ala Leu Met ArgCys Cys Leu Ile 35 40 45 Lys Trp Ile Leu Ser Ser Ala Ala Pro Gln Gly SerAsp Ser Ser Asp 50 55 60 Ser Glu Leu Glu Leu Ser Thr Val Arg His Gln ProGlu Gly Leu Asp 65 70 75 80 Gln Leu Gln Ala Gln Thr Lys Phe Thr Lys LysGlu Leu Gln Ser Leu 85 90 95 Tyr Arg Gly Phe Lys Asn Glu Cys Pro Thr GlyLeu Val Asp Glu Asp 100 105 110 Thr Phe Lys Leu Ile Tyr Ser Gln Phe PhePro Gln Gly Asp Ala Thr 115 120 125 Thr Tyr Ala His Phe Leu Phe Asn AlaPhe Asp Ala Asp Gly Asn Gly 130 135 140 Ala Ile His Phe Glu Asp Phe ValVal Gly Leu Ser Ile Leu Leu Arg 145 150 155 160 Gly Thr Val His Glu LysLeu Lys Trp Ala Phe Asn Leu Tyr Asp Ile 165 170 175 Asn Lys Asp Gly CysIle Thr Lys Glu Glu Met Leu Ala Ile Met Lys 180 185 190 Ser Ile Tyr AspMet Met Gly Arg His Thr Tyr Pro Ile Leu Arg Glu 195 200 205 Asp Ala ProLeu Glu His Val Glu Arg Phe Phe Gln Lys Met Asp Arg 210 215 220 Asn GlnAsp Gly Val Val Thr Ile Asp Glu Phe Leu Glu Thr Cys Gln 225 230 235 240Lys Asp Glu Asn Ile Met Asn Ser Met Gln Leu Phe Glu Asn Val Ile 245 250255 37 531 DNA Homo sapiens CDS (1)..(336) At position 495, n=any aminoacid 37 cac gag gtg gaa agc att tcg gct cag ctg gag gag gcc agc tct aca48 His Glu Val Glu Ser Ile Ser Ala Gln Leu Glu Glu Ala Ser Ser Thr 1 510 15 ggc ggt ttc ctg tac gct cag aac agc acc aag cgc agc att aaa gag 96Gly Gly Phe Leu Tyr Ala Gln Asn Ser Thr Lys Arg Ser Ile Lys Glu 20 25 30cgg ctc atg aag ctc ttg ccc tgc tca gct gcc aaa acg tcg tct cct 144 ArgLeu Met Lys Leu Leu Pro Cys Ser Ala Ala Lys Thr Ser Ser Pro 35 40 45 gctatt caa aac agc gtg gaa gat gaa ctg gag atg gcc acc gtc agg 192 Ala IleGln Asn Ser Val Glu Asp Glu Leu Glu Met Ala Thr Val Arg 50 55 60 cat cggccc gaa gcc ctt gag ctt ctg gaa gcc cag agc aaa ttt acc 240 His Arg ProGlu Ala Leu Glu Leu Leu Glu Ala Gln Ser Lys Phe Thr 65 70 75 80 aag aaagag ctt cag atc ctt tac aga gga ttt aag aac gta aga act 288 Lys Lys GluLeu Gln Ile Leu Tyr Arg Gly Phe Lys Asn Val Arg Thr 85 90 95 ttc ttt ttgact tta cct tca cac aat tcc cag agg agc att gag aaa 336 Phe Phe Leu ThrLeu Pro Ser His Asn Ser Gln Arg Ser Ile Glu Lys 100 105 110 tgagaggaaaagggggaaaa tatcccattc tatgagaagc cccatcatat gtatatttca 396 tactgatccttcccagatag gaatataatc agtatctgtg gactttgaat ctctgtggca 456 cacccatgctggcatactgt aattgcccat taaacaaana gtttttgaga aaaaaaaaaa 516 aaaaaaaaaaaaaaa 531 38 112 PRT Homo sapiens 38 His Glu Val Glu Ser Ile Ser Ala GlnLeu Glu Glu Ala Ser Ser Thr 1 5 10 15 Gly Gly Phe Leu Tyr Ala Gln AsnSer Thr Lys Arg Ser Ile Lys Glu 20 25 30 Arg Leu Met Lys Leu Leu Pro CysSer Ala Ala Lys Thr Ser Ser Pro 35 40 45 Ala Ile Gln Asn Ser Val Glu AspGlu Leu Glu Met Ala Thr Val Arg 50 55 60 His Arg Pro Glu Ala Leu Glu LeuLeu Glu Ala Gln Ser Lys Phe Thr 65 70 75 80 Lys Lys Glu Leu Gln Ile LeuTyr Arg Gly Phe Lys Asn Val Arg Thr 85 90 95 Phe Phe Leu Thr Leu Pro SerHis Asn Ser Gln Arg Ser Ile Glu Lys 100 105 110 39 2176 DNA Homo sapiensCDS (2)..(124) 39 t gaa agg ttc ttc gag aaa atg gac cgg aac cag gat ggggta gtg acc 49 Glu Arg Phe Phe Glu Lys Met Asp Arg Asn Gln Asp Gly ValVal Thr 1 5 10 15 att gaa gag ttc ctg gag gcc tgt cag aag gat gag aacatc atg agc 97 Ile Glu Glu Phe Leu Glu Ala Cys Gln Lys Asp Glu Asn IleMet Ser 20 25 30 tcc atg cag ctg ttt gag aat gtc atc taggacacgtccaaaggagt 144 Ser Met Gln Leu Phe Glu Asn Val Ile 35 40 gcatggccacagccacctcc acccccaaga aacctccatc ctgccaggag cagcctccaa 204 gaaacttttaaaaaatagat ttgcaaaaag tgaacagatt gctacacaca cacacacaca 264 cacacacacacacacacaca cacagccatt catctgggct ggcagagggg acagagttca 324 gggaggggctgagtctggct aggggccgag tccaggagcc ccagccagcc cttcccaggc 384 cagcgaggcgaggctgcctc tgggtgagtg gctgacagag caggtctgca ggccaccagc 444 tgctggatgtcaccaagaag gggctcgagt gcccctgcag gggagggtcc aatctccggt 504 gtgagcccacctcgtcccgt tctccattct gctttcttgc cacacagtgg gccggcccca 564 ggctcccctggtctcctccc cgtagccact ctctgcccac tacctatgct tctagaaagc 624 ccctcacctcaggaccccag agggaccagc tggggggcag gggggagagg gggtaatgga 684 ggccaagcctgcagctttct ggaaattctt ccctgggggt cccaggatcc cctgctactc 744 cactgacctggaagagctgg gtaccaggcc acccactgtg gggcaagcct gagtggtgag 804 gggccactgggccccattct ccctccatgg caggaaggcg ggggatttca agtttaggga 864 ttgggtcgtggtggagaatc tgagggcact ctctgccagc tccacagggt gggatgagcc 924 tctccttgccccagtcctgg ttcagtggga atgcagtggg tggggctgta cacaccctcc 984 agcacagactgttccctcca aggtcctctt aggtcccggg aggaacgtgg ttcagagact 1044 ggcagccagggagcccgggg cagagctcag aggagtctgg gaaggggcgt gtccctcctc 1104 ttcctgtagtgcccctccca tggcccagca gcttggctga gccccctctc ctgaagcagt 1164 gtcgccgtccctctgccttg cacaaaaagc acaagcattc cttagcagct caggcgcagc 1224 cctagtgggagcccagcaca ctgcttctcg gaggccaggc cctcctgctg gctgaggctt 1284 gggcccagtagccccaatat ggtggccctg gggaagaggc cttgggggtc tgctctgtgc 1344 ctgggatcagtggggcccca aagcccagcc cggctgacca acattcaaaa gcacaaaccc 1404 tggggactctgcttggctgt cccctccatc tggggatgga gaatgccagc ccaaagctgg 1464 agccaatggtgagggctgag agggctgtgg ctgggtggtc agcagaaacc cccaggagga 1524 gagagatgctgctcccgcct gattggggcc tcacccagaa ggaacccggt cccaggccgc 1584 atggcccctccaggaacatt cccacataat acattccatc acagccagcc cagctccact 1644 cagggctggcccggggagtc cccgtgtgcc ccaagaggct agccccaggg tgagcagggc 1704 cctcagaggaaaggcagtat ggcggaggcc atgggggccc ctcggcattc acacacagcc 1764 tggcctcccctgcggagctg catggacgcc tggctccagg ctccaggctg actgggggcc 1824 tctgcctccaggagggcatc agctttccct ggctcaggga tcttctccct cccctcaccc 1884 gctgcccagccctcccagct ggtgtcactc tgcctctaag gccaaggcct caggagagca 1944 tcaccaccacacccctgccg gccttggcct tggggccaga ctggctgcac agcccaacca 2004 ggaggggtctgcctcccacg ctgggacaca gaccggccgc atgtctgcat ggcagaagcg 2064 tctcccttggccacggcctg ggagggtggt tcctgttctc agcatccact aatattcagt 2124 cctgtatattttaataaaat aaacttgaca aaggaaaaaa aaaaaaaaaa aa 2176 40 41 PRT Homosapiens 40 Glu Arg Phe Phe Glu Lys Met Asp Arg Asn Gln Asp Gly Val ValThr 1 5 10 15 Ile Glu Glu Phe Leu Glu Ala Cys Gln Lys Asp Glu Asn IleMet Ser 20 25 30 Ser Met Gln Leu Phe Glu Asn Val Ile 35 40 41 2057 DNARattus sp. CDS (208)..(963) 41 tgctgcccaa ggctcctgct cctgccccaggactctgagg tgggccctaa aacccagcgc 60 tctctaaaga aaagccttgc cagcccctactcccggcccc caaccccagc aggtcgctgc 120 gccgccaggg ggcgctgtgt gagcgccctattctggccac ccggcgcccc ctcccacggc 180 ccaggcggga gcggggcgcc gggggcc atgcgg ggc caa ggc aga aag gag agt 234 Met Arg Gly Gln Gly Arg Lys Glu Ser1 5 ttg tcc gaa tcc cga gat ctg gac ggc tcc tat gac cag ctt acg ggc 282Leu Ser Glu Ser Arg Asp Leu Asp Gly Ser Tyr Asp Gln Leu Thr Gly 10 15 2025 cac cct cca ggg ccc agt aaa aaa gcc ctg aag cag cgt ttc ctc aag 330His Pro Pro Gly Pro Ser Lys Lys Ala Leu Lys Gln Arg Phe Leu Lys 30 35 40ctg ctg ccg tgc tgc ggg ccc caa gcc ctg ccc tca gtc agt gaa aac 378 LeuLeu Pro Cys Cys Gly Pro Gln Ala Leu Pro Ser Val Ser Glu Asn 45 50 55 agcgta gag gat gag ttt gaa tta tcc acg gtg tgt cac cga cct gag 426 Ser ValGlu Asp Glu Phe Glu Leu Ser Thr Val Cys His Arg Pro Glu 60 65 70 ggc ctggaa caa ctc cag gaa cag acc aag ttc aca cgc aga gag ctg 474 Gly Leu GluGln Leu Gln Glu Gln Thr Lys Phe Thr Arg Arg Glu Leu 75 80 85 cag gtc ctgtac cga ggc ttc aag aac gaa tgc ccc agt ggg att gtc 522 Gln Val Leu TyrArg Gly Phe Lys Asn Glu Cys Pro Ser Gly Ile Val 90 95 100 105 aac gaggag aac ttc aag cag att tat tct cag ttc ttt ccc caa gga 570 Asn Glu GluAsn Phe Lys Gln Ile Tyr Ser Gln Phe Phe Pro Gln Gly 110 115 120 gac tccagc aac tat gct act ttt ctc ttc aat gcc ttt gac acc aac 618 Asp Ser SerAsn Tyr Ala Thr Phe Leu Phe Asn Ala Phe Asp Thr Asn 125 130 135 cac gatggc tct gtc agt ttt gag gac ttt gtg gct ggt ttg tcg gtg 666 His Asp GlySer Val Ser Phe Glu Asp Phe Val Ala Gly Leu Ser Val 140 145 150 att cttcgg ggg acc ata gat gat aga ctg agc tgg gct ttc aac tta 714 Ile Leu ArgGly Thr Ile Asp Asp Arg Leu Ser Trp Ala Phe Asn Leu 155 160 165 tat gacctc aac aag gac ggc tgt atc aca aag gag gaa atg ctt gac 762 Tyr Asp LeuAsn Lys Asp Gly Cys Ile Thr Lys Glu Glu Met Leu Asp 170 175 180 185 attatg aag tcc atc tat gac atg atg ggc aag tac aca tac cct gcc 810 Ile MetLys Ser Ile Tyr Asp Met Met Gly Lys Tyr Thr Tyr Pro Ala 190 195 200 ctccgg gag gag gcc cca aga gaa cac gtg gag agc ttc ttc cag aag 858 Leu ArgGlu Glu Ala Pro Arg Glu His Val Glu Ser Phe Phe Gln Lys 205 210 215 atggac agg aac aag gac ggc gtg gtg acc atc gag gaa ttc atc gag 906 Met AspArg Asn Lys Asp Gly Val Val Thr Ile Glu Glu Phe Ile Glu 220 225 230 tcttgt caa cag gac gag aac atc atg agg tcc atg cag ctc tca ccc 954 Ser CysGln Gln Asp Glu Asn Ile Met Arg Ser Met Gln Leu Ser Pro 235 240 245 cttctc aac tgatacctag tgctgaggac acccctggtg tagggaccaa 1003 Leu Leu Asn 250gtggttctcc accttctagt cccactctag aaaccacatt agacagaagg tctcctgcta 1063tggtgctttc cccatcccta atctcttaga ttttcctcaa gactcccttc tcagagaaca 1123cgctctgtcc atgtccccag ctggcttctc agcctagcct ttgagggccc tgtggggagg 1183cggggacaag aaagcagaaa agtcttggcc ccgagccagt ggttaggtcc taggaattgg 1243ctggagtgga ggccagaaag cctgggcaga tgatgagagc ccagctgggc tgtcactgca 1303ggttccgggg cctacagccc tgggtcagca gagtatgagt tcccagactt tccagaaggt 1363ccttagcaat gtcccagaaa ttcaccgtac acttctcagt gtcttaggag ggcccgggat 1423ccagatgtct ggttcatccc tgaatcctct ccctccttct tgctcgtatg gtgggagtgg 1483tggccagggg aagatgagtg gtgtcccgga tgatgcctgt caaggtccca cctcccctcc 1543ggctgttctc atgacagctg tttggttctc catgacccct atctagatgt agaggcatgg 1603agtgagtcag ggatttcccg aacttgagtt ttaccactcc tcctagtggc tgccttaggg 1663gaatgggaag aacccagtgt gggggcaccc attagaatct ttgcccggct cctcacaatg 1723ccctagggtc ccctagggta cccgctccct ctgtttagtc tacccagaga tgctcctgag 1783ctcacctaga gggtagggac ggtaggctcc aggtccaacc tctccaggtc agcaccctgc 1843catgctgctg ctcctcatta acaaacctgc ttgtctcctc ctgcgcccct tctcagtcag 1903ccagggtctg aggggaaggg cctcccgttt ccccatccgt cagacatggt tgactgcttt 1963gcattttggg ctcttctatc tattttgtaa aataagacat cagatccaat aaaacacacg 2023gctatgcaca aaaaaaaaaa aaaaaaaaaa aaaa 2057 42 252 PRT Rattus sp. 42 MetArg Gly Gln Gly Arg Lys Glu Ser Leu Ser Glu Ser Arg Asp Leu 1 5 10 15Asp Gly Ser Tyr Asp Gln Leu Thr Gly His Pro Pro Gly Pro Ser Lys 20 25 30Lys Ala Leu Lys Gln Arg Phe Leu Lys Leu Leu Pro Cys Cys Gly Pro 35 40 45Gln Ala Leu Pro Ser Val Ser Glu Asn Ser Val Glu Asp Glu Phe Glu 50 55 60Leu Ser Thr Val Cys His Arg Pro Glu Gly Leu Glu Gln Leu Gln Glu 65 70 7580 Gln Thr Lys Phe Thr Arg Arg Glu Leu Gln Val Leu Tyr Arg Gly Phe 85 9095 Lys Asn Glu Cys Pro Ser Gly Ile Val Asn Glu Glu Asn Phe Lys Gln 100105 110 Ile Tyr Ser Gln Phe Phe Pro Gln Gly Asp Ser Ser Asn Tyr Ala Thr115 120 125 Phe Leu Phe Asn Ala Phe Asp Thr Asn His Asp Gly Ser Val SerPhe 130 135 140 Glu Asp Phe Val Ala Gly Leu Ser Val Ile Leu Arg Gly ThrIle Asp 145 150 155 160 Asp Arg Leu Ser Trp Ala Phe Asn Leu Tyr Asp LeuAsn Lys Asp Gly 165 170 175 Cys Ile Thr Lys Glu Glu Met Leu Asp Ile MetLys Ser Ile Tyr Asp 180 185 190 Met Met Gly Lys Tyr Thr Tyr Pro Ala LeuArg Glu Glu Ala Pro Arg 195 200 205 Glu His Val Glu Ser Phe Phe Gln LysMet Asp Arg Asn Lys Asp Gly 210 215 220 Val Val Thr Ile Glu Glu Phe IleGlu Ser Cys Gln Gln Asp Glu Asn 225 230 235 240 Ile Met Arg Ser Met GlnLeu Ser Pro Leu Leu Asn 245 250 43 26 PRT Artificial Sequence Xaas atpositions 2,5,6,9,17,25 and 26 may be Ile, Leu, Val or Met 43 Glu XaaXaa Xaa Xaa Xaa Xaa Xaa Xaa Asp Lys Asp Gly Asp Gly Xaa 1 5 10 15 XaaXaa Xaa Xaa Glu Phe Xaa Xaa Xaa Xaa 20 25 44 40 DNA Rattus sp. 44taatacgact cactataggg actggccatc ctgctctcag 40 45 40 DNA Rattus sp. 45attaaccctc actaaaggga cactactgtt taagctcaag 40 46 40 DNA Rattus sp. 46taatacgact cactataggg cacctcccct ccggctgttc 40 47 40 DNA Rattus sp. 47attaaccctc actaaaggga gagcagcagc atggcagggt 40 48 2413 DNA Simian sp.CDS (265)..(963) 48 gtcgacccac gcgtccggtg cgctgtggtt gcgggggggagccccgccag ccaaatgcca 60 ggatcagcat gagaggctgg actttagtcc aggtctgtcctcaccccggg ggaccgccgg 120 ctttgcaggg tgcagctgcg aggaactgct cacttttttccccttgcaag tctttgttcc 180 aagcctgacg ttgctacgat tctgtaatta actccctccactccaaaggg gtctggaggc 240 tgggatgctc tgccagctca gagg atg ttg act ctg gagtgg gag tcc gaa 291 Met Leu Thr Leu Glu Trp Glu Ser Glu 1 5 gga ctg caaaca gtg ggt att gtt gtg att ata tgt gca tct ctg aag 339 Gly Leu Gln ThrVal Gly Ile Val Val Ile Ile Cys Ala Ser Leu Lys 10 15 20 25 ctg ctt catttg ctg gga ctg att gat ttt tcg gaa gac agc gtg gaa 387 Leu Leu His LeuLeu Gly Leu Ile Asp Phe Ser Glu Asp Ser Val Glu 30 35 40 gat gaa ctg gagatg gcc act gtc agg cat cgg cct gag gcc ctt gag 435 Asp Glu Leu Glu MetAla Thr Val Arg His Arg Pro Glu Ala Leu Glu 45 50 55 ctt ctg gaa gcc cagagc aaa ttt acc aag aaa gag ctt cag atc ctt 483 Leu Leu Glu Ala Gln SerLys Phe Thr Lys Lys Glu Leu Gln Ile Leu 60 65 70 tac aga gga ttt aag aacgaa tgc ccc agt ggt gtt gtt aat gaa gaa 531 Tyr Arg Gly Phe Lys Asn GluCys Pro Ser Gly Val Val Asn Glu Glu 75 80 85 acc ttc aaa gag att tac tcgcag ttc ttt cca cag gga gac tct aca 579 Thr Phe Lys Glu Ile Tyr Ser GlnPhe Phe Pro Gln Gly Asp Ser Thr 90 95 100 105 aca tat gca cat ttt ctgttc aat gcg ttt gat acg gac cac aat gga 627 Thr Tyr Ala His Phe Leu PheAsn Ala Phe Asp Thr Asp His Asn Gly 110 115 120 gct gtg agt ttc gag gatttc atc aaa ggt ctt tcc att ttg ctc cgg 675 Ala Val Ser Phe Glu Asp PheIle Lys Gly Leu Ser Ile Leu Leu Arg 125 130 135 ggg aca gta caa gaa aaactc aat tgg gca ttt aat ctg tat gat ata 723 Gly Thr Val Gln Glu Lys LeuAsn Trp Ala Phe Asn Leu Tyr Asp Ile 140 145 150 aat aaa gat ggc tac atcact aaa gag gaa atg ctt gat ata atg aaa 771 Asn Lys Asp Gly Tyr Ile ThrLys Glu Glu Met Leu Asp Ile Met Lys 155 160 165 gca ata tac gac atg atgggt aaa tgt aca tat cct gtc ctc aaa gaa 819 Ala Ile Tyr Asp Met Met GlyLys Cys Thr Tyr Pro Val Leu Lys Glu 170 175 180 185 gat gca ccc aga caacac gtc gaa aca ttt ttt cag aaa atg gac aaa 867 Asp Ala Pro Arg Gln HisVal Glu Thr Phe Phe Gln Lys Met Asp Lys 190 195 200 aat aaa gat ggg gttgtt acc ata gat gag ttc att gaa agc tgc caa 915 Asn Lys Asp Gly Val ValThr Ile Asp Glu Phe Ile Glu Ser Cys Gln 205 210 215 aaa gat gaa aac ataatg cgc tcc atg cag ctc ttt gaa aat gtg att 963 Lys Asp Glu Asn Ile MetArg Ser Met Gln Leu Phe Glu Asn Val Ile 220 225 230 taacttgtcaactagatcct gaatccaaca gacaaatgtg aactattcta ccacccttaa 1023 agtcggagctaccactttta gcatagattg ctcagcttga cactgaagca tattatgcaa 1083 acaagctttgttttaatata aagcaatccc caaaagattt gagtttctca gttataaatt 1143 tgcatcctttccataatgcc actgagttca tgggatgttc taactcattt catactctgt 1203 gaatattcaaaagtaataga atctggcata tagttttatt gattccttag ccatgggatt 1263 attgaggctttcacatatca gtgattttaa aataccagtg ttttttgctc tcatttgtat 1323 gtattcagtcctaggatttt gaatggtttt ctaatatact gacatctgca tttaatttcc 1383 agaaattaaattaattttca tgtctgaatg ctgtaattcc atttatatac tttaagtaaa 1443 caaataagattactacaatt aaacacatag ttccagtttc tatggccttc ccttcccacc 1503 ttctattataaattaatttt atctggtatt tttaaacatt taaaaattta tcatcagata 1563 tcagcatatgcctaattatg cctaatgaaa cttaataagc atttaatttt ccatcataca 1623 ttatagccaaggcctatata ctatatataa ttttggattt gtttaatctt acaggctgtt 1683 ttccattgtatcatcaagtg gaagttcaag acggcatcaa acaaaacaag gatgtttaca 1743 gacatatgcaaagggtcagg atatctatcc tccagtatat gttaatgctt aataacaagt 1803 aatcctaacagcattaaagg ccaaatctgt cctctttccc ctgacttcct tacagcatgt 1863 ttatattacaagccattcag ggacaaagaa accttgacta ccccactgtc tactaggaac 1923 aaacaaacagcaagcaaaat tcactttgaa agcaccagtg gttccattac attgacaact 1983 actaccaagattcagtagaa aataagtgct caacaactaa tccagattac aatatgattt 2043 agtgcatcataaaattccaa caattcagat tatttttaat catctcagcc acaactgtaa 2103 agttgccacattactaaaga cacacacatc gtccctgttt tgtagaaata tcacaaagac 2163 caagaggctacagaaggagg aaatttgcaa ctgtctttgc aacaataaat caggtatcta 2223 ttctggtgtagagataggat gttgaaagct gccctgctat caccagtgta gaaattaaga 2283 gtagtacaatacatgtacac tgaaatttgc catcgcgtgt ttgtgtaaac tcaatgtgca 2343 cattttgtatttcaaaaaga aaaaataaaa gcaaaataaa atgttwawaa mwmwaaaaaa 2403 aaaaaaaaaa2413 49 233 PRT Simian sp. 49 Met Leu Thr Leu Glu Trp Glu Ser Glu GlyLeu Gln Thr Val Gly Ile 1 5 10 15 Val Val Ile Ile Cys Ala Ser Leu LysLeu Leu His Leu Leu Gly Leu 20 25 30 Ile Asp Phe Ser Glu Asp Ser Val GluAsp Glu Leu Glu Met Ala Thr 35 40 45 Val Arg His Arg Pro Glu Ala Leu GluLeu Leu Glu Ala Gln Ser Lys 50 55 60 Phe Thr Lys Lys Glu Leu Gln Ile LeuTyr Arg Gly Phe Lys Asn Glu 65 70 75 80 Cys Pro Ser Gly Val Val Asn GluGlu Thr Phe Lys Glu Ile Tyr Ser 85 90 95 Gln Phe Phe Pro Gln Gly Asp SerThr Thr Tyr Ala His Phe Leu Phe 100 105 110 Asn Ala Phe Asp Thr Asp HisAsn Gly Ala Val Ser Phe Glu Asp Phe 115 120 125 Ile Lys Gly Leu Ser IleLeu Leu Arg Gly Thr Val Gln Glu Lys Leu 130 135 140 Asn Trp Ala Phe AsnLeu Tyr Asp Ile Asn Lys Asp Gly Tyr Ile Thr 145 150 155 160 Lys Glu GluMet Leu Asp Ile Met Lys Ala Ile Tyr Asp Met Met Gly 165 170 175 Lys CysThr Tyr Pro Val Leu Lys Glu Asp Ala Pro Arg Gln His Val 180 185 190 GluThr Phe Phe Gln Lys Met Asp Lys Asn Lys Asp Gly Val Val Thr 195 200 205Ile Asp Glu Phe Ile Glu Ser Cys Gln Lys Asp Glu Asn Ile Met Arg 210 215220 Ser Met Gln Leu Phe Glu Asn Val Ile 225 230 50 1591 DNA Simian sp.CDS (265)..(963) 50 gtcgacccac gcgtccggtg cgctgtggtt gcgggggggagccccgccag ccaaatgcca 60 ggatcagcat gagaggctgg actttagtcc aggtctgtcctcaccccggg ggaccgccgg 120 ctttgcaggg tgcagctgcg aggaactgct cacttttttccccttgcaag tctttgttcc 180 aagcctgacg ttgctacgat tctgtaatta actccctccactccaaaggg gtctggaggc 240 tgggatgctc tgccagctca gagg atg ttg act ctg gagtgg gag tcc gaa 291 Met Leu Thr Leu Glu Trp Glu Ser Glu 1 5 gga ctg caaaca gtg ggt att gtt gtg att ata tgt gca tct ctg aag 339 Gly Leu Gln ThrVal Gly Ile Val Val Ile Ile Cys Ala Ser Leu Lys 10 15 20 25 ctg ctt catttg ctg gga ctg att gat ttt tcg gaa gac agc gtg gaa 387 Leu Leu His LeuLeu Gly Leu Ile Asp Phe Ser Glu Asp Ser Val Glu 30 35 40 gat gaa ctg gagatg gcc act gtc agg cat cgg cct gag gcc ctt gag 435 Asp Glu Leu Glu MetAla Thr Val Arg His Arg Pro Glu Ala Leu Glu 45 50 55 ctt ctg gaa gcc cagagc aaa ttt acc aag aaa gag ctt cag atc ctt 483 Leu Leu Glu Ala Gln SerLys Phe Thr Lys Lys Glu Leu Gln Ile Leu 60 65 70 tac aga gga ttt aag aacgaa tgc ccc agt ggt gtt gtt aat gaa gaa 531 Tyr Arg Gly Phe Lys Asn GluCys Pro Ser Gly Val Val Asn Glu Glu 75 80 85 acc ttc aaa gag att tac tcgcag ttc ttt cca cag gga gac tct aca 579 Thr Phe Lys Glu Ile Tyr Ser GlnPhe Phe Pro Gln Gly Asp Ser Thr 90 95 100 105 aca tat gca cat ttt ctgttc aat gcg ttt gat acg gac cac aat gga 627 Thr Tyr Ala His Phe Leu PheAsn Ala Phe Asp Thr Asp His Asn Gly 110 115 120 gct gtg agt ttc gag gatttc atc aaa ggt ctt tcc att ttg ctc cgg 675 Ala Val Ser Phe Glu Asp PheIle Lys Gly Leu Ser Ile Leu Leu Arg 125 130 135 ggg aca gta caa gaa aaactc aat tgg gca ttt aat ctg tat gat ata 723 Gly Thr Val Gln Glu Lys LeuAsn Trp Ala Phe Asn Leu Tyr Asp Ile 140 145 150 aat aaa gat ggc tac atcact aaa gag gaa atg ctt gat ata atg aaa 771 Asn Lys Asp Gly Tyr Ile ThrLys Glu Glu Met Leu Asp Ile Met Lys 155 160 165 gca ata tac gac atg atgggt aaa tgt aca tat cct gtc ctc aaa gaa 819 Ala Ile Tyr Asp Met Met GlyLys Cys Thr Tyr Pro Val Leu Lys Glu 170 175 180 185 gat gca ccc aga caacac gtc gaa aca ttt ttt cag gct gtt ttc cat 867 Asp Ala Pro Arg Gln HisVal Glu Thr Phe Phe Gln Ala Val Phe His 190 195 200 tgt atc atc aag tggaag ttc aag acg gca tca aac aaa aca agg atg 915 Cys Ile Ile Lys Trp LysPhe Lys Thr Ala Ser Asn Lys Thr Arg Met 205 210 215 ttt aca gac ata tgcaaa ggg tca gga tat cta tcc tcc agt ata tgt 963 Phe Thr Asp Ile Cys LysGly Ser Gly Tyr Leu Ser Ser Ser Ile Cys 220 225 230 taatgcttaataacaagtaa tcctaacagc attaaaggcc aaatctgtcc tctttcccct 1023 gacttccttacagcatgttt atattacaag ccattcaggg acaaagaaac cttgactacc 1083 ccactgtctactaggaacaa acaaacagca agcaaaattc actttgaaag caccagtggt 1143 tccattacattgacaactac taccaagatt cagtagaaaa taagtgctca acaactaatc 1203 cagattacaatatgatttag tgcatcataa aattccaaca attcagatta tttttaatca 1263 tctcagccacaactgtaaag ttgccacatt actaaagaca cacacatcgt ccctgttttg 1323 tagaaatatcacaaagacca agaggctaca gaaggaggaa atttgcaact gtctttgcaa 1383 caataaatcaggtatctatt ctggtgtaga gataggatgt tgaaagctgc cctgctatca 1443 ccagtgtagaaattaagagt agtacaatac atgtacactg aaatttgcca tcgcgtgttt 1503 gtgtaaactcaatgtgcaca ttttgtattt caaaaagaaa aaataaaagc aaaataaaat 1563 gttwawaamwmwaaaaaaaa aaaaaaaa 1591 51 233 PRT Simian sp. 51 Met Leu Thr Leu GluTrp Glu Ser Glu Gly Leu Gln Thr Val Gly Ile 1 5 10 15 Val Val Ile IleCys Ala Ser Leu Lys Leu Leu His Leu Leu Gly Leu 20 25 30 Ile Asp Phe SerGlu Asp Ser Val Glu Asp Glu Leu Glu Met Ala Thr 35 40 45 Val Arg His ArgPro Glu Ala Leu Glu Leu Leu Glu Ala Gln Ser Lys 50 55 60 Phe Thr Lys LysGlu Leu Gln Ile Leu Tyr Arg Gly Phe Lys Asn Glu 65 70 75 80 Cys Pro SerGly Val Val Asn Glu Glu Thr Phe Lys Glu Ile Tyr Ser 85 90 95 Gln Phe PhePro Gln Gly Asp Ser Thr Thr Tyr Ala His Phe Leu Phe 100 105 110 Asn AlaPhe Asp Thr Asp His Asn Gly Ala Val Ser Phe Glu Asp Phe 115 120 125 IleLys Gly Leu Ser Ile Leu Leu Arg Gly Thr Val Gln Glu Lys Leu 130 135 140Asn Trp Ala Phe Asn Leu Tyr Asp Ile Asn Lys Asp Gly Tyr Ile Thr 145 150155 160 Lys Glu Glu Met Leu Asp Ile Met Lys Ala Ile Tyr Asp Met Met Gly165 170 175 Lys Cys Thr Tyr Pro Val Leu Lys Glu Asp Ala Pro Arg Gln HisVal 180 185 190 Glu Thr Phe Phe Gln Ala Val Phe His Cys Ile Ile Lys TrpLys Phe 195 200 205 Lys Thr Ala Ser Asn Lys Thr Arg Met Phe Thr Asp IleCys Lys Gly 210 215 220 Ser Gly Tyr Leu Ser Ser Ser Ile Cys 225 230 522051 DNA Rattus sp. CDS (85)..(1305) 52 ggtggagcta agcactcact gcggtgctgccctgcgtctg cagagaacaa ggaaagcttc 60 tctgcagggc tgtcagctgc caaa atg aacggc gtg gaa ggg aac aac gag 111 Met Asn Gly Val Glu Gly Asn Asn Glu 1 5ctc cct ctc gct aac acc tcg acc tcc gcc ctt gtc ccg gaa gat ctg 159 LeuPro Leu Ala Asn Thr Ser Thr Ser Ala Leu Val Pro Glu Asp Leu 10 15 20 25gat ctg aag caa gac cag ccg ctc agc gag gaa act gac acg gtg cgg 207 AspLeu Lys Gln Asp Gln Pro Leu Ser Glu Glu Thr Asp Thr Val Arg 30 35 40 gagatg gag gct gca ggt gag gcc ggt gcg gag gga ggc gcg tcc ccc 255 Glu MetGlu Ala Ala Gly Glu Ala Gly Ala Glu Gly Gly Ala Ser Pro 45 50 55 gat tcggag cac tgc gac ccc cag ctc tgc ctc cga gtg gct gag aat 303 Asp Ser GluHis Cys Asp Pro Gln Leu Cys Leu Arg Val Ala Glu Asn 60 65 70 ggc tgt gctgcc gca gcg gga gag ggg ctg gag gat ggt ctg tct tca 351 Gly Cys Ala AlaAla Ala Gly Glu Gly Leu Glu Asp Gly Leu Ser Ser 75 80 85 tca aag tgt ggggac gca ccc ttg gcg tct gtg gca gcc aac gac agc 399 Ser Lys Cys Gly AspAla Pro Leu Ala Ser Val Ala Ala Asn Asp Ser 90 95 100 105 aat aaa aatggc tgt cag ctt gca ggg ccg ctc agc cct gct aag cca 447 Asn Lys Asn GlyCys Gln Leu Ala Gly Pro Leu Ser Pro Ala Lys Pro 110 115 120 aaa act ctggaa gcc agt ggt gca gtg ggc ctg ggg tcg cag atg atg 495 Lys Thr Leu GluAla Ser Gly Ala Val Gly Leu Gly Ser Gln Met Met 125 130 135 cca ggg ccgaag aag acc aag gta atg act acc aag ggc gcc atc tct 543 Pro Gly Pro LysLys Thr Lys Val Met Thr Thr Lys Gly Ala Ile Ser 140 145 150 gcg act acaggc aag gaa gga gaa gca ggg gcg gca atg cag gaa aag 591 Ala Thr Thr GlyLys Glu Gly Glu Ala Gly Ala Ala Met Gln Glu Lys 155 160 165 aag ggg gtgcag aaa gaa aaa aag gca gct gga gga ggg aaa gac gag 639 Lys Gly Val GlnLys Glu Lys Lys Ala Ala Gly Gly Gly Lys Asp Glu 170 175 180 185 act cgtcct aga gcc cct aag atc aat aac tgc atg gac tcc ctg gaa 687 Thr Arg ProArg Ala Pro Lys Ile Asn Asn Cys Met Asp Ser Leu Glu 190 195 200 gcc atcgat caa gag ctg tca aat gta aat gcg caa gct gac agg gcc 735 Ala Ile AspGln Glu Leu Ser Asn Val Asn Ala Gln Ala Asp Arg Ala 205 210 215 ttc ctccag ctg gaa cgc aaa ttt ggg cgg atg aga agg ctc cac atg 783 Phe Leu GlnLeu Glu Arg Lys Phe Gly Arg Met Arg Arg Leu His Met 220 225 230 cag cgccga agt ttc atc atc caa aac atc cca ggt ttc tgg gtc aca 831 Gln Arg ArgSer Phe Ile Ile Gln Asn Ile Pro Gly Phe Trp Val Thr 235 240 245 gcg tttcgg aac cac ccg caa ctg tca ccg atg atc agt ggc caa gat 879 Ala Phe ArgAsn His Pro Gln Leu Ser Pro Met Ile Ser Gly Gln Asp 250 255 260 265 gaagac atg atg agg tac atg atc aat tta gag gtg gag gag ctt aag 927 Glu AspMet Met Arg Tyr Met Ile Asn Leu Glu Val Glu Glu Leu Lys 270 275 280 caccca aga gca ggg tgc aaa ttt aag ttc atc ttc caa agc aac ccc 975 His ProArg Ala Gly Cys Lys Phe Lys Phe Ile Phe Gln Ser Asn Pro 285 290 295 tacttc cga aat gag ggg ctg gtc aaa gag tac gag cgc aga tcc tca 1023 Tyr PheArg Asn Glu Gly Leu Val Lys Glu Tyr Glu Arg Arg Ser Ser 300 305 310 ggtcga gtg gtg tcg ctc tct acg cca atc cgc tgg cac cgg ggt caa 1071 Gly ArgVal Val Ser Leu Ser Thr Pro Ile Arg Trp His Arg Gly Gln 315 320 325 gaaccc cag gcc cat atc cac agg aat aga gag ggg aac acg att ccc 1119 Glu ProGln Ala His Ile His Arg Asn Arg Glu Gly Asn Thr Ile Pro 330 335 340 345agt ttc ttc aat tgg ttc tca gac cac agc ctc cta gaa ttc gac aga 1167 SerPhe Phe Asn Trp Phe Ser Asp His Ser Leu Leu Glu Phe Asp Arg 350 355 360ata gct gaa att atc aaa ggg gag ctt tgg tcc aat ccc cta caa tac 1215 IleAla Glu Ile Ile Lys Gly Glu Leu Trp Ser Asn Pro Leu Gln Tyr 365 370 375tac ctg atg ggc gat ggg cca cgc aga gga gtt cga gtc cca cca agg 1263 TyrLeu Met Gly Asp Gly Pro Arg Arg Gly Val Arg Val Pro Pro Arg 380 385 390cag cca gtg gag agt ccc agg tcc ttc agg ttc cag tct ggc 1305 Gln Pro ValGlu Ser Pro Arg Ser Phe Arg Phe Gln Ser Gly 395 400 405 taagctctgccctcgtgaga agctcttaca gaagagtcct taccaccttc tcagcttggc 1365 tagcagcatgcagccttctg tctgctttct cttccttgga ttgtgtcctt tggttcttct 1425 aagtctccggtagtttcaag gttgtggctt ccaagtcttt gctcttcttt ctcttggcca 1485 tcacgatgtcctgcatagtg ttaatggtgt tccaagtgca tggcctccaa actgcttcta 1545 tgccaagctcacgtgctgta gtttgtactg cttttctttg catggcttgg ttcctgtctg 1605 tgatcttctaggttttttgt tttctttttt aaaagtggtt ctctatcaaa agaaagcttg 1665 acatatccttaccaagaact agccagattt catactgtgt tcccgatatc tatgtactgt 1725 gaagaactgtgagtttcgcc actgcaagat gggactgtat cccaatccag ccatcagccc 1785 aacaggacattccaagctgt caccaactga tcctagctgt cttcctgggc ctttgccatt 1845 taccctgctttttatctata gaatgagcag gtggctggta ggtgactact aggtaagagt 1905 gaagtattaggtgaggagtg ttttctgtca ccacattgtt cttgtaccaa tgcatcatga 1965 tcagcttggatcagctactg actgtctgat atttctaacc cccaacacaa aaaaaaaaaa 2025 aaaaaaaaaaaaaaaaaaaa aaaaaa 2051 53 407 PRT Rattus sp. 53 Met Asn Gly Val Glu GlyAsn Asn Glu Leu Pro Leu Ala Asn Thr Ser 1 5 10 15 Thr Ser Ala Leu ValPro Glu Asp Leu Asp Leu Lys Gln Asp Gln Pro 20 25 30 Leu Ser Glu Glu ThrAsp Thr Val Arg Glu Met Glu Ala Ala Gly Glu 35 40 45 Ala Gly Ala Glu GlyGly Ala Ser Pro Asp Ser Glu His Cys Asp Pro 50 55 60 Gln Leu Cys Leu ArgVal Ala Glu Asn Gly Cys Ala Ala Ala Ala Gly 65 70 75 80 Glu Gly Leu GluAsp Gly Leu Ser Ser Ser Lys Cys Gly Asp Ala Pro 85 90 95 Leu Ala Ser ValAla Ala Asn Asp Ser Asn Lys Asn Gly Cys Gln Leu 100 105 110 Ala Gly ProLeu Ser Pro Ala Lys Pro Lys Thr Leu Glu Ala Ser Gly 115 120 125 Ala ValGly Leu Gly Ser Gln Met Met Pro Gly Pro Lys Lys Thr Lys 130 135 140 ValMet Thr Thr Lys Gly Ala Ile Ser Ala Thr Thr Gly Lys Glu Gly 145 150 155160 Glu Ala Gly Ala Ala Met Gln Glu Lys Lys Gly Val Gln Lys Glu Lys 165170 175 Lys Ala Ala Gly Gly Gly Lys Asp Glu Thr Arg Pro Arg Ala Pro Lys180 185 190 Ile Asn Asn Cys Met Asp Ser Leu Glu Ala Ile Asp Gln Glu LeuSer 195 200 205 Asn Val Asn Ala Gln Ala Asp Arg Ala Phe Leu Gln Leu GluArg Lys 210 215 220 Phe Gly Arg Met Arg Arg Leu His Met Gln Arg Arg SerPhe Ile Ile 225 230 235 240 Gln Asn Ile Pro Gly Phe Trp Val Thr Ala PheArg Asn His Pro Gln 245 250 255 Leu Ser Pro Met Ile Ser Gly Gln Asp GluAsp Met Met Arg Tyr Met 260 265 270 Ile Asn Leu Glu Val Glu Glu Leu LysHis Pro Arg Ala Gly Cys Lys 275 280 285 Phe Lys Phe Ile Phe Gln Ser AsnPro Tyr Phe Arg Asn Glu Gly Leu 290 295 300 Val Lys Glu Tyr Glu Arg ArgSer Ser Gly Arg Val Val Ser Leu Ser 305 310 315 320 Thr Pro Ile Arg TrpHis Arg Gly Gln Glu Pro Gln Ala His Ile His 325 330 335 Arg Asn Arg GluGly Asn Thr Ile Pro Ser Phe Phe Asn Trp Phe Ser 340 345 350 Asp His SerLeu Leu Glu Phe Asp Arg Ile Ala Glu Ile Ile Lys Gly 355 360 365 Glu LeuTrp Ser Asn Pro Leu Gln Tyr Tyr Leu Met Gly Asp Gly Pro 370 375 380 ArgArg Gly Val Arg Val Pro Pro Arg Gln Pro Val Glu Ser Pro Arg 385 390 395400 Ser Phe Arg Phe Gln Ser Gly 405 54 4148 DNA Homo sapiens CDS(88)..(1329) 54 ggggtggtgc tagacgtttc gggcagagct cggccgctgc ggaggacaaggaactctccc 60 tctcccacta gtctgacttc ttccaaa atg agc ggc ctg gat ggg ggcaac aag 114 Met Ser Gly Leu Asp Gly Gly Asn Lys 1 5 ctc cct ctc gcc caaacc ggc ggc ctg gct gct ccc gac cat gcc tca 162 Leu Pro Leu Ala Gln ThrGly Gly Leu Ala Ala Pro Asp His Ala Ser 10 15 20 25 gga gat ccg gac ctagac cag tgc caa ggg ctc cgt gaa gaa acc gag 210 Gly Asp Pro Asp Leu AspGln Cys Gln Gly Leu Arg Glu Glu Thr Glu 30 35 40 gcg aca cag gtg atg gcgaac aca ggt ggg ggc agc ctg gag acc gtt 258 Ala Thr Gln Val Met Ala AsnThr Gly Gly Gly Ser Leu Glu Thr Val 45 50 55 gcg gag ggg ggt gca tcc caggat cct gtc gac tgt ggc ccc gcg ctc 306 Ala Glu Gly Gly Ala Ser Gln AspPro Val Asp Cys Gly Pro Ala Leu 60 65 70 cgc gtc cca gtt gcc ggg agt cgcggc ggt gca gcg acc aaa gcc ggg 354 Arg Val Pro Val Ala Gly Ser Arg GlyGly Ala Ala Thr Lys Ala Gly 75 80 85 cag gag gat gct cca cct tct acg aaaggt ctg gaa gca gcc tct gcc 402 Gln Glu Asp Ala Pro Pro Ser Thr Lys GlyLeu Glu Ala Ala Ser Ala 90 95 100 105 gcc gag gct gct gac agc agc cagaaa aat ggc tgt cag ctt gga gag 450 Ala Glu Ala Ala Asp Ser Ser Gln LysAsn Gly Cys Gln Leu Gly Glu 110 115 120 ccc cgt ggc cct gct ggg cag aaggct cta gaa gcc tgt ggc gca ggg 498 Pro Arg Gly Pro Ala Gly Gln Lys AlaLeu Glu Ala Cys Gly Ala Gly 125 130 135 ggc ttg ggg tct cag atg ata ccgggg aag aag gcc aag gaa gtg acg 546 Gly Leu Gly Ser Gln Met Ile Pro GlyLys Lys Ala Lys Glu Val Thr 140 145 150 act aaa aaa cgc gcc atc tcg gcagca gtg gaa aag gag gga gaa gca 594 Thr Lys Lys Arg Ala Ile Ser Ala AlaVal Glu Lys Glu Gly Glu Ala 155 160 165 ggg gcg gcg atg gag gaa aag aaggta gtg cag aag gaa aaa aag gtg 642 Gly Ala Ala Met Glu Glu Lys Lys ValVal Gln Lys Glu Lys Lys Val 170 175 180 185 gca gga ggg gtg aaa gag gagaca cgg ccc agg gcc ccg aag atc aat 690 Ala Gly Gly Val Lys Glu Glu ThrArg Pro Arg Ala Pro Lys Ile Asn 190 195 200 aac tgc atg gac tca ctg gaggcc atc gat caa gag ttg tca aac gta 738 Asn Cys Met Asp Ser Leu Glu AlaIle Asp Gln Glu Leu Ser Asn Val 205 210 215 aat gcc cag gct gac agg gccttc ctt cag ctt gag cgc aag ttt ggc 786 Asn Ala Gln Ala Asp Arg Ala PheLeu Gln Leu Glu Arg Lys Phe Gly 220 225 230 cgc atg cga agg ctc cac atgcag cgc aga agt ttc att atc cag aat 834 Arg Met Arg Arg Leu His Met GlnArg Arg Ser Phe Ile Ile Gln Asn 235 240 245 atc cca ggt ttc tgg gtt actgcc ttt cga aac cac ccc cag ctg tca 882 Ile Pro Gly Phe Trp Val Thr AlaPhe Arg Asn His Pro Gln Leu Ser 250 255 260 265 cct atg atc agt ggc caagat gaa gac atg ctg agg tac atg atc aat 930 Pro Met Ile Ser Gly Gln AspGlu Asp Met Leu Arg Tyr Met Ile Asn 270 275 280 ttg gag gtg gag gag cttaaa cac ccc aga gca ggc tgc aaa ttc aag 978 Leu Glu Val Glu Glu Leu LysHis Pro Arg Ala Gly Cys Lys Phe Lys 285 290 295 ttc atc ttt cag ggc aacccc tac ttc cga aat gag ggg ctt gtc aag 1026 Phe Ile Phe Gln Gly Asn ProTyr Phe Arg Asn Glu Gly Leu Val Lys 300 305 310 gaa tat gaa cgc aga tcctct ggc cgg gtg gtg tct ctt tcc act cca 1074 Glu Tyr Glu Arg Arg Ser SerGly Arg Val Val Ser Leu Ser Thr Pro 315 320 325 atc cgc tgg cac cga ggccaa gac ccc cag gct cat atc cac aga aac 1122 Ile Arg Trp His Arg Gly GlnAsp Pro Gln Ala His Ile His Arg Asn 330 335 340 345 cgg gaa ggg aac actatc cct agt ttc ttc aac tgg ttt tca gac cac 1170 Arg Glu Gly Asn Thr IlePro Ser Phe Phe Asn Trp Phe Ser Asp His 350 355 360 agc ctt cta gaa ttcgac aga att gca gag att atc aaa gga gaa ctg 1218 Ser Leu Leu Glu Phe AspArg Ile Ala Glu Ile Ile Lys Gly Glu Leu 365 370 375 tgg ccc aat ccc ctacaa tac tac ctg atg ggt gaa ggg ccc cgt aga 1266 Trp Pro Asn Pro Leu GlnTyr Tyr Leu Met Gly Glu Gly Pro Arg Arg 380 385 390 gga att cga ggc ccacca agg cag cca gtg gag agc gcc aga tcc ttc 1314 Gly Ile Arg Gly Pro ProArg Gln Pro Val Glu Ser Ala Arg Ser Phe 395 400 405 agg ttc cag tct ggctaatctctgt cctgtgagaa gcttctgcac aagtttcctt 1369 Arg Phe Gln Ser Gly 410accacctcct cttggaccta tgcttggcca acagcatgca gtcttccatc tgctttctct 1429tcatactgtg gattatcttt tcctttggtt ctaaatcttc agtaatcggt tgcaagattg 1489ttggcttacc tgcctgtgcc attcttcctc tgggccttca tgcttttctg cattgtgtta 1549acatgtttca agtgcatggc cttctacggc ttctatgcca agcgtatgat actatagata 1609tagtgtacca tactgccttt ctttgcatgg cttggaccct atctgtgacc atgctcttct 1669cccaatttaa gtggttctgt accacaaaga atcttgatac attttcacaa ataactgatt 1729gggcttcata ctttatgctg gctgtgtcct gatacccatg tacttatggt aagctatttg 1789ggtattacca ctgcaagaca aaactgatat cttaacccgg ccatcaaccc aaattggaca 1849ttccagacta ccaccaactg gatcccagct gccttcctgg gcttgtgcca tccaccctac 1909tggttatctg atagaacaag ctggtggctg atgggtgact gctaggcgtg actgaggtaa 1969tagatgaaaa gtgttctatg ttatcacatt ggttttcctg tacctttggt tactctacgt 2029catgaccagc tgctggtgag tatgaagcct gtgctatagc ccacccctac tcactctcac 2089cttctggttg aactttgctt aggccaccat tgtctgcctc atcaggaact atctgtagac 2149gtagctccca gggagctcac agcaacaccc cctaccacca ggatgggcag taatatgtga 2209cagagcccaa agcaaggctg gaacgcagtc ccttccagct tagtctttct gactcctagc 2269caacaaacca tccttaatgt gagcaacttc tttaggcatt tcctcttttc cccgcctgca 2329cccactctga acatgacaaa agttgccaga gttggggcat tgaggaagag atatttctgg 2389aatgtgagac ttgttatgcc tctgtctctt tctctccctc cccctcccct ctccctcccc 2449ctctccctcc catccctttt cttccctttc actctgaagc agttttagct tattaacaga 2509aaacaaaact ggcaaagcag gctttttgtt taatttgctc tttccctgat tgtgttcaga 2569gagaaaggtt atgattaaat gggctccaga tctcttattg cccttattcc tccaccccac 2629ttcttttagc aaggtctgaa agtttcaaag ggagacctat aggttaattg tttagttata 2689ggcagtgtta aattaggcag attttgacat atttatcttt ttaccccatc cattctacca 2749aaacctgtgt atttcttgag tttttagttt gagaagctgg aaagagagag aagggcctca 2809cagtgatggg ttcaggacgg gtcaaaggca aaggcctttg tgatgtgagc aaaggcaacc 2869aaaacttagc ctcactccac ttttctaaag atggaaattc ttttttgggc cttggactgc 2929ttctagggta gcattttgta ggtcactctt ctcctttgta ctattttgtt tctgccctga 2989tgtcccttgg gtctccatcc tactgcctgg ctttcttggc cctcatttct cagcttctgc 3049atttccttcc ctgctcctaa caaatgaaga agcaggctgc agcctgcatt gtggaagatc 3109tccagcctcc ttgtagggga taaggggatg tgtagcatct gtgtggattt tcacggacaa 3169gttccagtag gtgggacagt gatgccgtca aggcttagtt atgatcatgt gtggtgataa 3229agaccatcca ccatcaccct tttccccttt ggttttgaag gccttgccct aagctacctg 3289agggtttagg aggtctgaac acacacagtg gagaggttaa tctaggttgg gaaactgagt 3349aaaagtccag agcaggaatg agcctgctgt ggcgtgggtt tggaaaggct cacaggaaag 3409aacctgcagg atcaggggtg ggaggggagg cccctgaggt gctctccagg gaagaggggc 3469tggggtttaa atagcatgct tggaggaaga ttttccttca atttttccta agtccttgaa 3529ttcaccagta gatttttgta aacaaaatgt aagtcgatgt tttctctcaa ttatcctagg 3589agtgaccttt atatgtgtgg aagattaatg gtatatgctc cttatgtcac tgtttttgag 3649taaaatccat ttcctttctc tgtttcagcc tatgacaaaa ttgatgttta caggcctgct 3709ttttgcttat aattgacaac atgtgcaaaa ataccaaatt tgtgtcctgt gcagtatgaa 3769gaattcagtg aatattcatt aatgtattag cttgttttgc tctctgttca tatatggctc 3829tattcttaga aatataattt gaatgtgatc tttcaatagt ctgaatattt tacaaattat 3889agctatgtct tgtgaaaata acctcaaaaa gaaaaatacg actctgttgt cttacttgat 3949atttcttgcc ctagtaatgt acttgacatt tatgttccta agcagtgtaa gtaccagtag 4009aatttctctg tcaaactcaa tgatcattta gtacttttgt cttctcccat gtgcttgaag 4069gaaaaataaa gtgtcactac cgtatttctt gttttcatca aaaaataaaa ataatttaaa 4129aaacaaaaaa aaaaaaaaa 4148 55 414 PRT Homo sapiens 55 Met Ser Gly Leu AspGly Gly Asn Lys Leu Pro Leu Ala Gln Thr Gly 1 5 10 15 Gly Leu Ala AlaPro Asp His Ala Ser Gly Asp Pro Asp Leu Asp Gln 20 25 30 Cys Gln Gly LeuArg Glu Glu Thr Glu Ala Thr Gln Val Met Ala Asn 35 40 45 Thr Gly Gly GlySer Leu Glu Thr Val Ala Glu Gly Gly Ala Ser Gln 50 55 60 Asp Pro Val AspCys Gly Pro Ala Leu Arg Val Pro Val Ala Gly Ser 65 70 75 80 Arg Gly GlyAla Ala Thr Lys Ala Gly Gln Glu Asp Ala Pro Pro Ser 85 90 95 Thr Lys GlyLeu Glu Ala Ala Ser Ala Ala Glu Ala Ala Asp Ser Ser 100 105 110 Gln LysAsn Gly Cys Gln Leu Gly Glu Pro Arg Gly Pro Ala Gly Gln 115 120 125 LysAla Leu Glu Ala Cys Gly Ala Gly Gly Leu Gly Ser Gln Met Ile 130 135 140Pro Gly Lys Lys Ala Lys Glu Val Thr Thr Lys Lys Arg Ala Ile Ser 145 150155 160 Ala Ala Val Glu Lys Glu Gly Glu Ala Gly Ala Ala Met Glu Glu Lys165 170 175 Lys Val Val Gln Lys Glu Lys Lys Val Ala Gly Gly Val Lys GluGlu 180 185 190 Thr Arg Pro Arg Ala Pro Lys Ile Asn Asn Cys Met Asp SerLeu Glu 195 200 205 Ala Ile Asp Gln Glu Leu Ser Asn Val Asn Ala Gln AlaAsp Arg Ala 210 215 220 Phe Leu Gln Leu Glu Arg Lys Phe Gly Arg Met ArgArg Leu His Met 225 230 235 240 Gln Arg Arg Ser Phe Ile Ile Gln Asn IlePro Gly Phe Trp Val Thr 245 250 255 Ala Phe Arg Asn His Pro Gln Leu SerPro Met Ile Ser Gly Gln Asp 260 265 270 Glu Asp Met Leu Arg Tyr Met IleAsn Leu Glu Val Glu Glu Leu Lys 275 280 285 His Pro Arg Ala Gly Cys LysPhe Lys Phe Ile Phe Gln Gly Asn Pro 290 295 300 Tyr Phe Arg Asn Glu GlyLeu Val Lys Glu Tyr Glu Arg Arg Ser Ser 305 310 315 320 Gly Arg Val ValSer Leu Ser Thr Pro Ile Arg Trp His Arg Gly Gln 325 330 335 Asp Pro GlnAla His Ile His Arg Asn Arg Glu Gly Asn Thr Ile Pro 340 345 350 Ser PhePhe Asn Trp Phe Ser Asp His Ser Leu Leu Glu Phe Asp Arg 355 360 365 IleAla Glu Ile Ile Lys Gly Glu Leu Trp Pro Asn Pro Leu Gln Tyr 370 375 380Tyr Leu Met Gly Glu Gly Pro Arg Arg Gly Ile Arg Gly Pro Pro Arg 385 390395 400 Gln Pro Val Glu Ser Ala Arg Ser Phe Arg Phe Gln Ser Gly 405 41056 2643 DNA Rattus sp. CDS (1)..(801) 56 ctg aaa ggg gcg agg ccc agg gtggtg aac tcc acc tgc agt gac ttc 48 Leu Lys Gly Ala Arg Pro Arg Val ValAsn Ser Thr Cys Ser Asp Phe 1 5 10 15 aac cat ggc tca gct ctg cac atcgct gcc tcg aat ctg tgc ctg ggc 96 Asn His Gly Ser Ala Leu His Ile AlaAla Ser Asn Leu Cys Leu Gly 20 25 30 gcc gcc aaa tgt tta ctg gag cat ggtgcc aac cca gcg ctg agg aat 144 Ala Ala Lys Cys Leu Leu Glu His Gly AlaAsn Pro Ala Leu Arg Asn 35 40 45 cga aaa gga cag gta cca gcg gaa gtg gtccca gac ccc atg gac atg 192 Arg Lys Gly Gln Val Pro Ala Glu Val Val ProAsp Pro Met Asp Met 50 55 60 tcc ctt gac aag gca gag gca gcc ctg gtg gccaag gaa ttg cgg acg 240 Ser Leu Asp Lys Ala Glu Ala Ala Leu Val Ala LysGlu Leu Arg Thr 65 70 75 80 ctg cta gaa gag gct gtg cca ctg tcc tgc accctt cct aaa gtc aca 288 Leu Leu Glu Glu Ala Val Pro Leu Ser Cys Thr LeuPro Lys Val Thr 85 90 95 cta ccc aac tat gac aac gtc cca ggc aat ctc atgctc agc gcg ctg 336 Leu Pro Asn Tyr Asp Asn Val Pro Gly Asn Leu Met LeuSer Ala Leu 100 105 110 ggc ctg cgt cta gga gac cga gtg ctc ctc gat ggccag aag acg ggc 384 Gly Leu Arg Leu Gly Asp Arg Val Leu Leu Asp Gly GlnLys Thr Gly 115 120 125 acg ctg agg ttc tgc ggg acc acc gag ttc gcc agtggc cag tgg gtg 432 Thr Leu Arg Phe Cys Gly Thr Thr Glu Phe Ala Ser GlyGln Trp Val 130 135 140 ggc gtg gag cta gat gaa ccg gaa ggc aag aac gacggc agc gtt ggg 480 Gly Val Glu Leu Asp Glu Pro Glu Gly Lys Asn Asp GlySer Val Gly 145 150 155 160 ggt gtc cgg tac ttc atc tgc cct ccc aag cagggt ctc ttt gca tct 528 Gly Val Arg Tyr Phe Ile Cys Pro Pro Lys Gln GlyLeu Phe Ala Ser 165 170 175 gtg tcc aag gtc tcc aag gca gtg gat gca cccccc tca tct gtt acc 576 Val Ser Lys Val Ser Lys Ala Val Asp Ala Pro ProSer Ser Val Thr 180 185 190 tcc acg ccc cgc act ccc cgg atg gac ttc tcccgt gta acg ggc aaa 624 Ser Thr Pro Arg Thr Pro Arg Met Asp Phe Ser ArgVal Thr Gly Lys 195 200 205 ggc cgg agg gaa cac aaa ggg aag aag aag tcccca tct tcc cca tct 672 Gly Arg Arg Glu His Lys Gly Lys Lys Lys Ser ProSer Ser Pro Ser 210 215 220 ctg ggc agc ctg cag cag cgt gaa ggg gcc aaagct gaa gtt gga gac 720 Leu Gly Ser Leu Gln Gln Arg Glu Gly Ala Lys AlaGlu Val Gly Asp 225 230 235 240 caa gtc ctt gtg gca ggc cag aac agg gattgt gcg ttt cta tgg gaa 768 Gln Val Leu Val Ala Gly Gln Asn Arg Asp CysAla Phe Leu Trp Glu 245 250 255 gac aga ctt tgc tcc agg tta ctg gta tggcat tgaactggac cagcccacgg 821 Asp Arg Leu Cys Ser Arg Leu Leu Val TrpHis 260 265 gcaagcatga cggctctgtg ttcggtgtcc ggtactttac ctgtgccccgaggcacgggg 881 tctttgcacc agcatctcgt atccagagga ttggtggatc cactgatccccctggagaca 941 gtgttggagc aaaaaaagtg catcaagtga caatgacaca gcccaaacgcaccttcacaa 1001 cagtccggac cccaaaggac attgcatcag agaactctat ctccaggttactcttctgct 1061 gctggtttcc ttggatgctg agggcggaga tgcagtctta gagacctggatacctgacac 1121 agagacagag tcccctctag catctcctga cacaaggaga ccccagtcaccctaagatag 1181 agattcccag tgacacctcc agaatagaaa ccccgttagc cagccctcgattactgaggt 1241 cccattatta acagatctcc catgacgact cccccaaata cagacctcatgttaccccaa 1301 aagagattcc ctgagtagca ccttcaggct agtccctgtc ccctacccctcagagcagat 1361 ttcccccaat aaacattttc cacatcaccc aagggatgct gaccctctccacgacaggac 1421 gttcttgagt taccagtgga ttagagtccc atgaatgaag accccccccaccccggttct 1481 ccttaagcat aggtcatacc tccagaatag ccagccacat cactatccccatgtaacatc 1541 agtctcctca aaatggcgtg aggtcactag aaagacctta tactctcctctccttctcag 1601 agatgccctc cattcactta agtccctgtt ctcacccctg aacaagacacctaattaacc 1661 ggcccactca cctcaattac aaacaccaaa atcgtcctgg aagcatgaattacaggacag 1721 caagtcttcc tgccctctgc acccttgaga aacccccagt gccttgtatgaagcccaccc 1781 cacatggccc acagtccctg tgctggccaa ggctcccaga aaattctctattttttaaag 1841 taataacttc cccccctttg gggggatccc caaatttgga gaccccattctagaacactg 1901 gggagttcaa attccagaga gaatatatat tatatataat ccccaattccccatgcttcc 1961 aagccctaca atctctagaa gaccccaaat ttctaattcc caggacttcccctacccaag 2021 tcacagaatc ttcaaatccc cagggaatcc caaacttaag ataccaatcccaaaccctca 2081 ggaaatcccc caacacaagg tccttaggac cgggaggaag gaacctgttgccaggagaac 2141 atcccaggct ctcagggcat ctcaaacctg actcccaggc accaggagaccccaaacaga 2201 aagtcccatc tttggaacaa ggataggact ctaataccct tagtccatggatctttaatt 2261 tcccaacctc caaactccat gggccccacc ctcaagggaa cccccaagatccaaatctct 2321 gataactaat atgtgcaggg ccccagggct ctaacaggac cccaaatcatggagtcccta 2381 cttcaatcta ccttctggtc acaggtccaa gacactaaat ctgagtcattggccccaaag 2441 gacttcacag cacctgggcc agactaacag cctgagggag aacctgagggccccgtgggt 2501 ccagagcaga cctggggccc tgaccaccaa ggacagctca cgactgccccttcactgcat 2561 gtccctaaac tcagcatgac tcctgtcctc ttcaataaag acgtttctatggcaaaaaaa 2621 aaaaaaaaaa aaaaaaaaaa aa 2643 57 267 PRT Rattus sp. 57Leu Lys Gly Ala Arg Pro Arg Val Val Asn Ser Thr Cys Ser Asp Phe 1 5 1015 Asn His Gly Ser Ala Leu His Ile Ala Ala Ser Asn Leu Cys Leu Gly 20 2530 Ala Ala Lys Cys Leu Leu Glu His Gly Ala Asn Pro Ala Leu Arg Asn 35 4045 Arg Lys Gly Gln Val Pro Ala Glu Val Val Pro Asp Pro Met Asp Met 50 5560 Ser Leu Asp Lys Ala Glu Ala Ala Leu Val Ala Lys Glu Leu Arg Thr 65 7075 80 Leu Leu Glu Glu Ala Val Pro Leu Ser Cys Thr Leu Pro Lys Val Thr 8590 95 Leu Pro Asn Tyr Asp Asn Val Pro Gly Asn Leu Met Leu Ser Ala Leu100 105 110 Gly Leu Arg Leu Gly Asp Arg Val Leu Leu Asp Gly Gln Lys ThrGly 115 120 125 Thr Leu Arg Phe Cys Gly Thr Thr Glu Phe Ala Ser Gly GlnTrp Val 130 135 140 Gly Val Glu Leu Asp Glu Pro Glu Gly Lys Asn Asp GlySer Val Gly 145 150 155 160 Gly Val Arg Tyr Phe Ile Cys Pro Pro Lys GlnGly Leu Phe Ala Ser 165 170 175 Val Ser Lys Val Ser Lys Ala Val Asp AlaPro Pro Ser Ser Val Thr 180 185 190 Ser Thr Pro Arg Thr Pro Arg Met AspPhe Ser Arg Val Thr Gly Lys 195 200 205 Gly Arg Arg Glu His Lys Gly LysLys Lys Ser Pro Ser Ser Pro Ser 210 215 220 Leu Gly Ser Leu Gln Gln ArgGlu Gly Ala Lys Ala Glu Val Gly Asp 225 230 235 240 Gln Val Leu Val AlaGly Gln Asn Arg Asp Cys Ala Phe Leu Trp Glu 245 250 255 Asp Arg Leu CysSer Arg Leu Leu Val Trp His 260 265 58 2929 DNA Rattus sp. CDS(1)..(810) 58 gct gac tct acc tct aga tgg gct gag gcc ctc aga gaa atctct ggt 48 Ala Asp Ser Thr Ser Arg Trp Ala Glu Ala Leu Arg Glu Ile SerGly 1 5 10 15 cgc tta gct gaa atg cct gca gat agt gga tac cct gca tacctt ggt 96 Arg Leu Ala Glu Met Pro Ala Asp Ser Gly Tyr Pro Ala Tyr LeuGly 20 25 30 gcc cga ctg gct tct ttc tat gag cga gca ggc aga gtg aaa tgtctt 144 Ala Arg Leu Ala Ser Phe Tyr Glu Arg Ala Gly Arg Val Lys Cys Leu35 40 45 gga aac cct gag aga gaa ggg agt gtc agc att gta gga gca gtt tct192 Gly Asn Pro Glu Arg Glu Gly Ser Val Ser Ile Val Gly Ala Val Ser 5055 60 cca cct ggt ggt gat ttt tct gat cca gtc aca tct gct act ctg ggt240 Pro Pro Gly Gly Asp Phe Ser Asp Pro Val Thr Ser Ala Thr Leu Gly 6570 75 80 att gtt cag gtg ttc tgg ggc ttg gat aag aag cta gct cag cgc aag288 Ile Val Gln Val Phe Trp Gly Leu Asp Lys Lys Leu Ala Gln Arg Lys 8590 95 cac ttc ccg tcc gtc aac tgg ctc att agc tac agc aag tac atg cgc336 His Phe Pro Ser Val Asn Trp Leu Ile Ser Tyr Ser Lys Tyr Met Arg 100105 110 gcc ctg gac gag tac tat gac aaa cac ttc aca gag ttc gtg cct ctg384 Ala Leu Asp Glu Tyr Tyr Asp Lys His Phe Thr Glu Phe Val Pro Leu 115120 125 agg acc aaa gct aag gag att ctg cag gaa gag gag gat ctg gcg gaa432 Arg Thr Lys Ala Lys Glu Ile Leu Gln Glu Glu Glu Asp Leu Ala Glu 130135 140 atc gtg cag ctc gtg gga aag gcg tct tta gca gag aca gat aaa atc480 Ile Val Gln Leu Val Gly Lys Ala Ser Leu Ala Glu Thr Asp Lys Ile 145150 155 160 acc ctg gag gta gca aaa ctt atc aaa gat gac ttc cta caa caaaat 528 Thr Leu Glu Val Ala Lys Leu Ile Lys Asp Asp Phe Leu Gln Gln Asn165 170 175 ggg tac act cct tat gac agg ttc tgt cca ttc tat aag acg gtgggg 576 Gly Tyr Thr Pro Tyr Asp Arg Phe Cys Pro Phe Tyr Lys Thr Val Gly180 185 190 atg ctg tcc aac atg att tca ttc tat gat atg gcc cgc cgg gctgtg 624 Met Leu Ser Asn Met Ile Ser Phe Tyr Asp Met Ala Arg Arg Ala Val195 200 205 gag acc acc gcc cag agt gac aat aag atc aca tgg tcc att atccgt 672 Glu Thr Thr Ala Gln Ser Asp Asn Lys Ile Thr Trp Ser Ile Ile Arg210 215 220 gag cac atg ggg gag att ctc tat aaa ctt tcc tcc atg aaa ttcaag 720 Glu His Met Gly Glu Ile Leu Tyr Lys Leu Ser Ser Met Lys Phe Lys225 230 235 240 gat cca gtg aag gat ggc gag gca aag atc aag gcc gac tacgca cag 768 Asp Pro Val Lys Asp Gly Glu Ala Lys Ile Lys Ala Asp Tyr AlaGln 245 250 255 ctt ctt gaa gat atg cag aac gca ttc cgt agc ctg gaa gat810 Leu Leu Glu Asp Met Gln Asn Ala Phe Arg Ser Leu Glu Asp 260 265 270tagaactgtg acttctctcc tcctcttccg cagctcatat gtgtatattt tcctgaattt 870ctcatctcca accctttgct tccatattgt gcagctttga gactagtgcc tcgtgcgttc 930tcgttcattt tgctgtttct ttggtaggtc ttataaaaca cacattcctg tgctccgctg 990tctgaaggag ctcctgacct ttgtctgaag tggtgaatgt agtgcatatg atacacagtg 1050taacatacac attgtaacat atacgttctg taaacttgta tgtaaggtga ctaccccttc 1110cctcctctcc agtaaactgt aaacaggact actgcatgtg ctctattggg gatggaaggc 1170cagatctcca taccgtggac aggtacataa ggaaactaga ccacttgcaa cttagtgttt 1230gttgagtaac cattttgcag gaagtatttc catttaaaaa acaaaagatt aatgttccaa 1290ttatttgtag cttccccagt atcaatcagg actgtttgtg gcgcacttgg gaactatttt 1350gttttcctaa cagacgtttg caaggctgaa cgtaatagat aaatcagttc cctctgaaag 1410tgtgaaagta aaaagagagc taggtggtca gacttaaatt gacatcgtct tgtttaagca 1470tattttattt cactgagaga tttaatatca aggactttta tatactcaat tactaggaaa 1530tcttttttta agtacaattt aaaaatcatt gaaaatgtga tccacatcat agccattttc 1590cttatattta gtcagatgag ctcagagtgg ggagggtgtg ggttagaata ccacaaggac 1650acgcagcagt gcctgcaggc agtgtggccg ggggccagag cggcattgtt ttcacgaggt 1710acgtgtgtgg cgtgtgtgtt tgcttgttga cactctgaaa acagcaagct taccagttcc 1770aggaaatatt ttgttttctt tcactggctc agaaagctcc tcaaagtacc tggtccctga 1830agcttcctat ctgttaatag agacgagaga ggttcttaaa tttaactggt gacaaaacaa 1890aaagaaaaaa aagatcgatt tttgtcttgc tgttttggtg tgtttaaata ataattccat 1950atttgcataa cgaggctcgc ttctgagagc ttggagatcg tgctccctct tcactctccg 2010gggtgataat gctggcgcca tgctacctct tcaggagggg aaggggattg aacatggcta 2070acactctcaa gtacacaagc gtaacgacaa agtatttatt ttaagccttg gtatgttgtt 2130taaattatta ggtggtgcat ttcttatggt cttttgggta gacatagtat acacttcaga 2190tgtaatgtgt aaatccttgc tagtgcatgt ctacacgata gactgctatt caagaaggat 2250attcttccac ataacaattt aaaaactatt aaatcagata tggattatgc aatgacttgt 2310tgagaggtgg attaacggtg ctgcttaatc agtttgcttc caatatggct tcgtatccag 2370aagccctgac tagtggagat gagaaagatt tcaaaacctg tctgcctaca cctaccagca 2430acctaggctt gtgatcagaa tgaatgatcc caagaaacta cttgaccaag tgtgttttgt 2490tgtcctggat ttgagatgtg cgttcttcct ccctctgaga ctgttgatgt atgagtgtga 2550agaagttaca gaaacaacgc tcagattttc acggtaactt tccctctgcc cacactgtag 2610agtttcagat tgttcactga tagtgcttct ttcgtaagga tgtgttaaaa tatagcagtc 2670tttttaaaag attatgcagt tctctattta ttgtgctgtg cctggtccta agtgcagccg 2730gttaaacaag tttcatatgt atttttccag tgttaaatct catacctatg ccctttggaa 2790agctccatcc tgaacaatga atagaagagg ctatataaat tgcctcctta tccttaagat 2850ttcactatct ttatgttaag agtaatgtat aattattaaa atctatgaaa aataaaaagt 2910ggatttaaat taagagatc 2929 59 270 PRT Rattus sp. 59 Ala Asp Ser Thr SerArg Trp Ala Glu Ala Leu Arg Glu Ile Ser Gly 1 5 10 15 Arg Leu Ala GluMet Pro Ala Asp Ser Gly Tyr Pro Ala Tyr Leu Gly 20 25 30 Ala Arg Leu AlaSer Phe Tyr Glu Arg Ala Gly Arg Val Lys Cys Leu 35 40 45 Gly Asn Pro GluArg Glu Gly Ser Val Ser Ile Val Gly Ala Val Ser 50 55 60 Pro Pro Gly GlyAsp Phe Ser Asp Pro Val Thr Ser Ala Thr Leu Gly 65 70 75 80 Ile Val GlnVal Phe Trp Gly Leu Asp Lys Lys Leu Ala Gln Arg Lys 85 90 95 His Phe ProSer Val Asn Trp Leu Ile Ser Tyr Ser Lys Tyr Met Arg 100 105 110 Ala LeuAsp Glu Tyr Tyr Asp Lys His Phe Thr Glu Phe Val Pro Leu 115 120 125 ArgThr Lys Ala Lys Glu Ile Leu Gln Glu Glu Glu Asp Leu Ala Glu 130 135 140Ile Val Gln Leu Val Gly Lys Ala Ser Leu Ala Glu Thr Asp Lys Ile 145 150155 160 Thr Leu Glu Val Ala Lys Leu Ile Lys Asp Asp Phe Leu Gln Gln Asn165 170 175 Gly Tyr Thr Pro Tyr Asp Arg Phe Cys Pro Phe Tyr Lys Thr ValGly 180 185 190 Met Leu Ser Asn Met Ile Ser Phe Tyr Asp Met Ala Arg ArgAla Val 195 200 205 Glu Thr Thr Ala Gln Ser Asp Asn Lys Ile Thr Trp SerIle Ile Arg 210 215 220 Glu His Met Gly Glu Ile Leu Tyr Lys Leu Ser SerMet Lys Phe Lys 225 230 235 240 Asp Pro Val Lys Asp Gly Glu Ala Lys IleLys Ala Asp Tyr Ala Gln 245 250 255 Leu Leu Glu Asp Met Gln Asn Ala PheArg Ser Leu Glu Asp 260 265 270 60 1489 DNA Rattus sp. CDS (1)..(1053)60 gca cgg ctc ccg gcc ccg gag cat gcg cga cag cag ccc ctc ctc tcc 48Ala Arg Leu Pro Ala Pro Glu His Ala Arg Gln Gln Pro Leu Leu Ser 1 5 1015 ggc cct gag ccc gga tcg tcc gcc cgg gtt cca gtt ccc ggc gtg gcc 96Gly Pro Glu Pro Gly Ser Ser Ala Arg Val Pro Val Pro Gly Val Ala 20 25 30agt agg cgg cag ccg cga ggc ggc aag cca ccc agc ggg gac ggc ctg 144 SerArg Arg Gln Pro Arg Gly Gly Lys Pro Pro Ser Gly Asp Gly Leu 35 40 45 gagtcg ggc ccc tct cca cgc ccc ctt ctc cac gcg cgc ggg gag gca 192 Glu SerGly Pro Ser Pro Arg Pro Leu Leu His Ala Arg Gly Glu Ala 50 55 60 ggg ctccac cgc cag tct gga agg gtt cca cat aca gga acg gcc tac 240 Gly Leu HisArg Gln Ser Gly Arg Val Pro His Thr Gly Thr Ala Tyr 65 70 75 80 ttc gcagat gag ccc acc gag gct cag gct ccg ggc gga ttc tgc gtg 288 Phe Ala AspGlu Pro Thr Glu Ala Gln Ala Pro Gly Gly Phe Cys Val 85 90 95 tca ccc tcgctc ctt ggg gtc cgc tgg ccg gcc tgt gcc acc cgg acg 336 Ser Pro Ser LeuLeu Gly Val Arg Trp Pro Ala Cys Ala Thr Arg Thr 100 105 110 ccc ggc tcactg cct ctg tct ccc cca tca gcg cag ccc cgg acg cta 384 Pro Gly Ser LeuPro Leu Ser Pro Pro Ser Ala Gln Pro Arg Thr Leu 115 120 125 tgg ccc acccct cca gct ggc ccc tcg agt agg atg gta gca cgt aac 432 Trp Pro Thr ProPro Ala Gly Pro Ser Ser Arg Met Val Ala Arg Asn 130 135 140 cag gtg gcagcc gac aat gcg atc tcc ccg gca tca gag ccc cga cgg 480 Gln Val Ala AlaAsp Asn Ala Ile Ser Pro Ala Ser Glu Pro Arg Arg 145 150 155 160 cgg ccagag cca tcc tcg tcc tcg tct tcg tcc tcg ccg gcg gcc ccg 528 Arg Pro GluPro Ser Ser Ser Ser Ser Ser Ser Ser Pro Ala Ala Pro 165 170 175 gcg cgtccc cgg ccc tgc ccg gtg gtc ccg gcc ccg gct ccg ggc gac 576 Ala Arg ProArg Pro Cys Pro Val Val Pro Ala Pro Ala Pro Gly Asp 180 185 190 act cacttc cgc acc ttc cgc tcc cac tct gat tac cgg cgc atc acg 624 Thr His PheArg Thr Phe Arg Ser His Ser Asp Tyr Arg Arg Ile Thr 195 200 205 cgg accagc gct ctc ctg gac gcc tgc ggc ttc tac tgg gga ccc ctg 672 Arg Thr SerAla Leu Leu Asp Ala Cys Gly Phe Tyr Trp Gly Pro Leu 210 215 220 agc gtgcat ggg gcg cac gaa cgg ctg cgt gcc gag ccc gtg ggc acc 720 Ser Val HisGly Ala His Glu Arg Leu Arg Ala Glu Pro Val Gly Thr 225 230 235 240 ttcttg gtg cgc gac agt cgc cag cgg aac tgc ttc ttc gcg ctc agc 768 Phe LeuVal Arg Asp Ser Arg Gln Arg Asn Cys Phe Phe Ala Leu Ser 245 250 255 gtgaag atg gct tcg ggc ccc acg agc att cgt gtg cac ttc cag gcc 816 Val LysMet Ala Ser Gly Pro Thr Ser Ile Arg Val His Phe Gln Ala 260 265 270 ggccgc ttc cac ctg gac ggc agc cgc gag acc ttc gac tgc ctc ttc 864 Gly ArgPhe His Leu Asp Gly Ser Arg Glu Thr Phe Asp Cys Leu Phe 275 280 285 gagctg ctg gag cac tac gtg gcg gcg ccg cgc cgc atg ttg ggg gcc 912 Glu LeuLeu Glu His Tyr Val Ala Ala Pro Arg Arg Met Leu Gly Ala 290 295 300 ccactg cgc cag cgc cgc gtg cgg ccg ctg cag gag ctg tgt cgc cag 960 Pro LeuArg Gln Arg Arg Val Arg Pro Leu Gln Glu Leu Cys Arg Gln 305 310 315 320cgc atc gtg gcc gcc gtg ggt cgc gag aac ctg gca cgc atc cct ctt 1008 ArgIle Val Ala Ala Val Gly Arg Glu Asn Leu Ala Arg Ile Pro Leu 325 330 335aac ccg gta ctc cgt gac tac ctg agt tcc ttc ccc ttc cag atc 1053 Asn ProVal Leu Arg Asp Tyr Leu Ser Ser Phe Pro Phe Gln Ile 340 345 350tgaccggctg ccgccgtgcc cgcagcatta agtgggagcg ccttattatt tcttattatt 1113aattattatt atttttctgg aaccacgtgg gagccctccc cgcctaggtc ggagggagtg 1173ggtgtggagg gtgagatgcc tcccacttct ggctggagac cttatcccgc ctctcggggg 1233gcctcccctc ctggtgctcc ctcccggtcc ccctggttgt agcagcttgt gtctggggcc 1293aggacctgaa ctccacgcct acctctccat gtttacatgt tcccagtatc tttgcacaaa 1353ccaggggtgg gggagggtct ctggcttcat ttttctgctg tgcagaatat tctattttat 1413atttttacat ccagtttaga taataaactt tattatgaaa gttttttttt taaagaaaaa 1473aaaaaaaaaa aaaaaa 1489 61 351 PRT Rattus sp. 61 Ala Arg Leu Pro Ala ProGlu His Ala Arg Gln Gln Pro Leu Leu Ser 1 5 10 15 Gly Pro Glu Pro GlySer Ser Ala Arg Val Pro Val Pro Gly Val Ala 20 25 30 Ser Arg Arg Gln ProArg Gly Gly Lys Pro Pro Ser Gly Asp Gly Leu 35 40 45 Glu Ser Gly Pro SerPro Arg Pro Leu Leu His Ala Arg Gly Glu Ala 50 55 60 Gly Leu His Arg GlnSer Gly Arg Val Pro His Thr Gly Thr Ala Tyr 65 70 75 80 Phe Ala Asp GluPro Thr Glu Ala Gln Ala Pro Gly Gly Phe Cys Val 85 90 95 Ser Pro Ser LeuLeu Gly Val Arg Trp Pro Ala Cys Ala Thr Arg Thr 100 105 110 Pro Gly SerLeu Pro Leu Ser Pro Pro Ser Ala Gln Pro Arg Thr Leu 115 120 125 Trp ProThr Pro Pro Ala Gly Pro Ser Ser Arg Met Val Ala Arg Asn 130 135 140 GlnVal Ala Ala Asp Asn Ala Ile Ser Pro Ala Ser Glu Pro Arg Arg 145 150 155160 Arg Pro Glu Pro Ser Ser Ser Ser Ser Ser Ser Ser Pro Ala Ala Pro 165170 175 Ala Arg Pro Arg Pro Cys Pro Val Val Pro Ala Pro Ala Pro Gly Asp180 185 190 Thr His Phe Arg Thr Phe Arg Ser His Ser Asp Tyr Arg Arg IleThr 195 200 205 Arg Thr Ser Ala Leu Leu Asp Ala Cys Gly Phe Tyr Trp GlyPro Leu 210 215 220 Ser Val His Gly Ala His Glu Arg Leu Arg Ala Glu ProVal Gly Thr 225 230 235 240 Phe Leu Val Arg Asp Ser Arg Gln Arg Asn CysPhe Phe Ala Leu Ser 245 250 255 Val Lys Met Ala Ser Gly Pro Thr Ser IleArg Val His Phe Gln Ala 260 265 270 Gly Arg Phe His Leu Asp Gly Ser ArgGlu Thr Phe Asp Cys Leu Phe 275 280 285 Glu Leu Leu Glu His Tyr Val AlaAla Pro Arg Arg Met Leu Gly Ala 290 295 300 Pro Leu Arg Gln Arg Arg ValArg Pro Leu Gln Glu Leu Cys Arg Gln 305 310 315 320 Arg Ile Val Ala AlaVal Gly Arg Glu Asn Leu Ala Arg Ile Pro Leu 325 330 335 Asn Pro Val LeuArg Asp Tyr Leu Ser Ser Phe Pro Phe Gln Ile 340 345 350 62 1194 DNARattus sp. CDS (130)..(765) 62 ggcacggctc ccggccccgg agcatgcgcgacagcagccc cggaaccccc agccgcggcg 60 ccccgcgtcc cgccgccagc gcagccccggacgctatggc ccacccctcc agctggcccc 120 tcgagtagg atg gta gca cgt aac caggtg gca gcc gac aat gcg atc tcc 171 Met Val Ala Arg Asn Gln Val Ala AlaAsp Asn Ala Ile Ser 1 5 10 ccg gca tca gag ccc cga cgg cgg cca gag ccatcc tcg tcc tcg tct 219 Pro Ala Ser Glu Pro Arg Arg Arg Pro Glu Pro SerSer Ser Ser Ser 15 20 25 30 tcg tcc tcg ccg gcg gcc ccg gcg cgt ccc cggccc tgc ccg gtg gtc 267 Ser Ser Ser Pro Ala Ala Pro Ala Arg Pro Arg ProCys Pro Val Val 35 40 45 ccg gcc ccg gct ccg ggc gac act cac ttc cgc accttc cgc tcc cac 315 Pro Ala Pro Ala Pro Gly Asp Thr His Phe Arg Thr PheArg Ser His 50 55 60 tct gat tac cgg cgc atc acg cgg acc agc gct ctc ctggac gcc tgc 363 Ser Asp Tyr Arg Arg Ile Thr Arg Thr Ser Ala Leu Leu AspAla Cys 65 70 75 ggc ttc tac tgg gga ccc ctg agc gtg cat ggg gcg cac gaacgg ctg 411 Gly Phe Tyr Trp Gly Pro Leu Ser Val His Gly Ala His Glu ArgLeu 80 85 90 cgt gcc gag ccc gtg ggc acc ttc ttg gtg cgc gac agt cgc cagcgg 459 Arg Ala Glu Pro Val Gly Thr Phe Leu Val Arg Asp Ser Arg Gln Arg95 100 105 110 aac tgc ttc ttc gcg ctc agc gtg aag atg gct tcg ggc cccacg agc 507 Asn Cys Phe Phe Ala Leu Ser Val Lys Met Ala Ser Gly Pro ThrSer 115 120 125 att cgt gtg cac ttc cag gcc ggc cgc ttc cac ctg gac ggcagc cgc 555 Ile Arg Val His Phe Gln Ala Gly Arg Phe His Leu Asp Gly SerArg 130 135 140 gag acc ttc gac tgc ctc ttc gag ctg ctg gag cac tac gtggcg gcg 603 Glu Thr Phe Asp Cys Leu Phe Glu Leu Leu Glu His Tyr Val AlaAla 145 150 155 ccg cgc cgc atg ttg ggg gcc cca ctg cgc cag cgc cgc gtgcgg ccg 651 Pro Arg Arg Met Leu Gly Ala Pro Leu Arg Gln Arg Arg Val ArgPro 160 165 170 ctg cag gag ctg tgt cgc cag cgc atc gtg gcc gcc gtg ggtcgc gag 699 Leu Gln Glu Leu Cys Arg Gln Arg Ile Val Ala Ala Val Gly ArgGlu 175 180 185 190 aac ctg gca cgc atc cct ctt aac ccg gta ctc cgt gactac ctg agt 747 Asn Leu Ala Arg Ile Pro Leu Asn Pro Val Leu Arg Asp TyrLeu Ser 195 200 205 tcc ttc ccc ttc cag atc tgaccggctg ccgccgtgcccgcagcatta 795 Ser Phe Pro Phe Gln Ile 210 agtgggagcg ccttattatttcttattatt aattattatt atttttctgg aaccacgtgg 855 gagccctccc cgcctaggtcggagggagtg ggtgtggagg gtgagatgcc tcccacttct 915 ggctggagac cttatcccgcctctcggggg gcctcccctc ctggtgctcc ctcccggtcc 975 ccctggttgt agcagcttgtgtctggggcc aggacctgaa ctccacgcct acctctccat 1035 gtttacatgt tcccagtatctttgcacaaa ccaggggtgg gggagggtct ctggcttcat 1095 ttttctgctg tgcagaatattctattttat atttttacat ccagtttaga taataaactt 1155 tattatgaaa gttttttttttaaaaaaaaa aaaaaaaaa 1194 63 212 PRT Rattus sp. 63 Met Val Ala Arg AsnGln Val Ala Ala Asp Asn Ala Ile Ser Pro Ala 1 5 10 15 Ser Glu Pro ArgArg Arg Pro Glu Pro Ser Ser Ser Ser Ser Ser Ser 20 25 30 Ser Pro Ala AlaPro Ala Arg Pro Arg Pro Cys Pro Val Val Pro Ala 35 40 45 Pro Ala Pro GlyAsp Thr His Phe Arg Thr Phe Arg Ser His Ser Asp 50 55 60 Tyr Arg Arg IleThr Arg Thr Ser Ala Leu Leu Asp Ala Cys Gly Phe 65 70 75 80 Tyr Trp GlyPro Leu Ser Val His Gly Ala His Glu Arg Leu Arg Ala 85 90 95 Glu Pro ValGly Thr Phe Leu Val Arg Asp Ser Arg Gln Arg Asn Cys 100 105 110 Phe PheAla Leu Ser Val Lys Met Ala Ser Gly Pro Thr Ser Ile Arg 115 120 125 ValHis Phe Gln Ala Gly Arg Phe His Leu Asp Gly Ser Arg Glu Thr 130 135 140Phe Asp Cys Leu Phe Glu Leu Leu Glu His Tyr Val Ala Ala Pro Arg 145 150155 160 Arg Met Leu Gly Ala Pro Leu Arg Gln Arg Arg Val Arg Pro Leu Gln165 170 175 Glu Leu Cys Arg Gln Arg Ile Val Ala Ala Val Gly Arg Glu AsnLeu 180 185 190 Ala Arg Ile Pro Leu Asn Pro Val Leu Arg Asp Tyr Leu SerSer Phe 195 200 205 Pro Phe Gln Ile 210 64 600 DNA Rattus sp. CDS(52)..(336) 64 cttccaaaga ctgcagcgcc tcagggccca ggtttcaaca gattcttcaa aatg cca 57 Met Pro 1 tcc caa atg gag cat gcc atg gaa acc atg atg ctt acattt cac agg 105 Ser Gln Met Glu His Ala Met Glu Thr Met Met Leu Thr PheHis Arg 5 10 15 ttt gca ggg gaa aaa aac tac ttg aca aag gag gac ctg agagtg ctc 153 Phe Ala Gly Glu Lys Asn Tyr Leu Thr Lys Glu Asp Leu Arg ValLeu 20 25 30 atg gaa agg gag ttc cct ggg ttt ttg gaa aat caa aag gac cctctg 201 Met Glu Arg Glu Phe Pro Gly Phe Leu Glu Asn Gln Lys Asp Pro Leu35 40 45 50 gct gtg gac aaa ata atg aaa gac ctg gac cag tgc cga gat ggaaaa 249 Ala Val Asp Lys Ile Met Lys Asp Leu Asp Gln Cys Arg Asp Gly Lys55 60 65 gtg ggc ttc cag agc ttt cta tca cta gtg gcg ggg ctc atc att gca297 Val Gly Phe Gln Ser Phe Leu Ser Leu Val Ala Gly Leu Ile Ile Ala 7075 80 tgc aat gac tat ttt gta gta cac atg aag cag aag aag taggccaact 346Cys Asn Asp Tyr Phe Val Val His Met Lys Gln Lys Lys 85 90 95 ggagccctggtacccacacc ttgatgcgtc ctctcccatg gggtcaactg aggaatctgc 406 cccactgcttcctgtgagca gatcaggacc cttaggaaat gtgcaaataa catccaactc 466 caattcgacaagcagagaaa gaaaagttaa tccaatgaca gaggagcttt cgagttttat 526 attgtttgcatccggttgcc ctcaataaag aaagtctttt tttttaagtt ccgaaaaaaa 586 aaaaaaaaaaaaaa 600 65 95 PRT Rattus sp. 65 Met Pro Ser Gln Met Glu His Ala Met GluThr Met Met Leu Thr Phe 1 5 10 15 His Arg Phe Ala Gly Glu Lys Asn TyrLeu Thr Lys Glu Asp Leu Arg 20 25 30 Val Leu Met Glu Arg Glu Phe Pro GlyPhe Leu Glu Asn Gln Lys Asp 35 40 45 Pro Leu Ala Val Asp Lys Ile Met LysAsp Leu Asp Gln Cys Arg Asp 50 55 60 Gly Lys Val Gly Phe Gln Ser Phe LeuSer Leu Val Ala Gly Leu Ile 65 70 75 80 Ile Ala Cys Asn Asp Tyr Phe ValVal His Met Lys Gln Lys Lys 85 90 95 66 639 DNA Rattus sp. CDS(1)..(636) 66 atg gcg tac gcc tat ctc ttc aag tac atc atc atc ggc gacaca ggt 48 Met Ala Tyr Ala Tyr Leu Phe Lys Tyr Ile Ile Ile Gly Asp ThrGly 1 5 10 15 gtt ggt aaa tcg tgc tta ttg cta cag ttt aca gac aag aggttt cag 96 Val Gly Lys Ser Cys Leu Leu Leu Gln Phe Thr Asp Lys Arg PheGln 20 25 30 ccg gtg cat gac ctc aca att ggt gta gag ttt ggt gct cga atgata 144 Pro Val His Asp Leu Thr Ile Gly Val Glu Phe Gly Ala Arg Met Ile35 40 45 acc att gat ggg aaa cag ata aaa ctc cag atc tgg gat aca gca ggg192 Thr Ile Asp Gly Lys Gln Ile Lys Leu Gln Ile Trp Asp Thr Ala Gly 5055 60 cag gag tcc ttt cgt tct atc aca agg tca tat tac aga ggt gca gcg240 Gln Glu Ser Phe Arg Ser Ile Thr Arg Ser Tyr Tyr Arg Gly Ala Ala 6570 75 80 ggg gct tta cta gtg tat gat att aca agg aga gac acg ttc aac cac288 Gly Ala Leu Leu Val Tyr Asp Ile Thr Arg Arg Asp Thr Phe Asn His 8590 95 ttg aca acc tgg tta gaa gac gcc cgt cag cat tcc aat tcc aac atg336 Leu Thr Thr Trp Leu Glu Asp Ala Arg Gln His Ser Asn Ser Asn Met 100105 110 gtc atc atg ctt att gga aat aaa agt gac tta gaa tct agg aga gaa384 Val Ile Met Leu Ile Gly Asn Lys Ser Asp Leu Glu Ser Arg Arg Glu 115120 125 gtg aaa aag gaa gaa ggt gaa gct ttt gca cga gag cat gga ctt atc432 Val Lys Lys Glu Glu Gly Glu Ala Phe Ala Arg Glu His Gly Leu Ile 130135 140 ttc atg gaa act tct gcc aag act gct tct aat gta gag gag gca ttt480 Phe Met Glu Thr Ser Ala Lys Thr Ala Ser Asn Val Glu Glu Ala Phe 145150 155 160 att aac aca gca aaa gaa att tat gaa aaa atc caa gaa ggg gtcttt 528 Ile Asn Thr Ala Lys Glu Ile Tyr Glu Lys Ile Gln Glu Gly Val Phe165 170 175 gac att aat aat gag gca aac ggc atc aaa att ggc cct cag catgct 576 Asp Ile Asn Asn Glu Ala Asn Gly Ile Lys Ile Gly Pro Gln His Ala180 185 190 gct acc aat gca tct cac gga ggc aac caa gga ggg cag cag gcaggg 624 Ala Thr Asn Ala Ser His Gly Gly Asn Gln Gly Gly Gln Gln Ala Gly195 200 205 gga ggc tgc tgc tga 639 Gly Gly Cys Cys 210 67 212 PRTRattus sp. 67 Met Ala Tyr Ala Tyr Leu Phe Lys Tyr Ile Ile Ile Gly AspThr Gly 1 5 10 15 Val Gly Lys Ser Cys Leu Leu Leu Gln Phe Thr Asp LysArg Phe Gln 20 25 30 Pro Val His Asp Leu Thr Ile Gly Val Glu Phe Gly AlaArg Met Ile 35 40 45 Thr Ile Asp Gly Lys Gln Ile Lys Leu Gln Ile Trp AspThr Ala Gly 50 55 60 Gln Glu Ser Phe Arg Ser Ile Thr Arg Ser Tyr Tyr ArgGly Ala Ala 65 70 75 80 Gly Ala Leu Leu Val Tyr Asp Ile Thr Arg Arg AspThr Phe Asn His 85 90 95 Leu Thr Thr Trp Leu Glu Asp Ala Arg Gln His SerAsn Ser Asn Met 100 105 110 Val Ile Met Leu Ile Gly Asn Lys Ser Asp LeuGlu Ser Arg Arg Glu 115 120 125 Val Lys Lys Glu Glu Gly Glu Ala Phe AlaArg Glu His Gly Leu Ile 130 135 140 Phe Met Glu Thr Ser Ala Lys Thr AlaSer Asn Val Glu Glu Ala Phe 145 150 155 160 Ile Asn Thr Ala Lys Glu IleTyr Glu Lys Ile Gln Glu Gly Val Phe 165 170 175 Asp Ile Asn Asn Glu AlaAsn Gly Ile Lys Ile Gly Pro Gln His Ala 180 185 190 Ala Thr Asn Ala SerHis Gly Gly Asn Gln Gly Gly Gln Gln Ala Gly 195 200 205 Gly Gly Cys Cys210 68 816 DNA Rattus sp. CDS (1)..(813) 68 atg gtg ctg ctc aag gaa tatcgg gtc atc ctg cct gtg tct gta gat 48 Met Val Leu Leu Lys Glu Tyr ArgVal Ile Leu Pro Val Ser Val Asp 1 5 10 15 gag tat caa gtg ggg cag ctgtac tct gtg gct gaa gcc agt aaa aat 96 Glu Tyr Gln Val Gly Gln Leu TyrSer Val Ala Glu Ala Ser Lys Asn 20 25 30 gaa act ggt ggt ggg gaa ggt gtggag gtc ctg gtg aac gag ccc tac 144 Glu Thr Gly Gly Gly Glu Gly Val GluVal Leu Val Asn Glu Pro Tyr 35 40 45 gag aag gat gat ggc gag aaa ggc cagtac aca cac aag atc tac cac 192 Glu Lys Asp Asp Gly Glu Lys Gly Gln TyrThr His Lys Ile Tyr His 50 55 60 tta cag agc aaa gtt ccc acg ttt gtt cgaatg ctg gcc cca gaa ggc 240 Leu Gln Ser Lys Val Pro Thr Phe Val Arg MetLeu Ala Pro Glu Gly 65 70 75 80 gcc ctg aat ata cat gag aaa gcc tgg aatgcc tac cct tac tgc aga 288 Ala Leu Asn Ile His Glu Lys Ala Trp Asn AlaTyr Pro Tyr Cys Arg 85 90 95 acc gtt att aca aat gag tac atg aag gaa gacttt ctc att aaa att 336 Thr Val Ile Thr Asn Glu Tyr Met Lys Glu Asp PheLeu Ile Lys Ile 100 105 110 gaa acc tgg cac aag cca gac ctt ggc acc caggag aat gtg cat aaa 384 Glu Thr Trp His Lys Pro Asp Leu Gly Thr Gln GluAsn Val His Lys 115 120 125 ctg gag cct gag gca tgg aaa cat gtg gaa gctata tat ata gac atc 432 Leu Glu Pro Glu Ala Trp Lys His Val Glu Ala IleTyr Ile Asp Ile 130 135 140 gct gat cga agc caa gta ctt agc aag gat tacaag gca gag gaa gac 480 Ala Asp Arg Ser Gln Val Leu Ser Lys Asp Tyr LysAla Glu Glu Asp 145 150 155 160 cca gca aaa ttt aaa tct atc aaa aca ggacga gga cca ttg ggc ccg 528 Pro Ala Lys Phe Lys Ser Ile Lys Thr Gly ArgGly Pro Leu Gly Pro 165 170 175 aat tgg aag caa gaa ctt gtc aat cag aaggac tgc cca tat atg tgt 576 Asn Trp Lys Gln Glu Leu Val Asn Gln Lys AspCys Pro Tyr Met Cys 180 185 190 gca tac aaa ctg gtt act gtc aag ttc aagtgg tgg ggc ttg cag aac 624 Ala Tyr Lys Leu Val Thr Val Lys Phe Lys TrpTrp Gly Leu Gln Asn 195 200 205 aaa gtg gaa aac ttt ata cat aag caa gagaag cgt ctg ttt aca aac 672 Lys Val Glu Asn Phe Ile His Lys Gln Glu LysArg Leu Phe Thr Asn 210 215 220 ttt cac agg cag ctg ttc tgt tgg ctt gataaa tgg gtt gat ctg act 720 Phe His Arg Gln Leu Phe Cys Trp Leu Asp LysTrp Val Asp Leu Thr 225 230 235 240 atg gat gac att cgg agg atg gaa gaagag acg aag aga cag ctg gat 768 Met Asp Asp Ile Arg Arg Met Glu Glu GluThr Lys Arg Gln Leu Asp 245 250 255 gag atg aga caa aag gac ccc gtg aaagga atg aca gca gat gac tag 816 Glu Met Arg Gln Lys Asp Pro Val Lys GlyMet Thr Ala Asp Asp 260 265 270 69 2263 DNA Simian sp. 69 cgctctcctcctcccctttc tctagcagta gccttcttaa tgtagtttaa tggctttaca 60 aagaaagccaggcagaggag cacttctcag tggctgtggt cggaccatga cctagctgac 120 catgaacttggaagggcttg aaatgatagc agttctgatc gtcattgtgc tttttgttaa 180 attattggaacagtttgggc tgattgaagc aggtttagaa gacagcgtgg aagatgaact 240 ggagatggccactgtcaggc atcggcctga ggcccttgag cttctggaag cccagagcaa 300 atttaccaagaaagagcttc agatccttta cagaggattt aagaacgaat gccccagtgg 360 tgttgttaatgaagaaacct tcaaagagat ttactcgcag ttctttccac agggagactc 420 tacaacatatgcacattttc tgttcaatgc gtttgatacg gaccacaatg gagctgtgag 480 tttcgaggatttcatcaaag gtctttccat tttgctccgg gggacagtac aagaaaaact 540 caattgggcatttaatctgt atgatataaa taaagatggc tacatcacta aagaggaaat 600 gcttgatataatgaaagcaa tatacgacat gatgggtaaa tgtacatatc ctgtcctcaa 660 agaagatgcacccagacaac acgtcgaaac attttttcag aaaatggaca aaaataaaga 720 tggggttgttaccatagatg agttcattga aagctgccaa aaagatgaaa acataatgcg 780 ctccatgcagctctttgaaa atgtgattta acttgtcaac tagatcctga atccaacaga 840 caaatgtgaactattctacc acccttaaag tcggagctac cacttttagc atagattgct 900 cagcttgacactgaagcata ttatgcaaac aagctttgtt ttaatataaa gcaatcccca 960 aaagatttgagtttctcagt tataaatttg catcctttcc ataatgccac tgagttcatg 1020 ggatgttctaactcatttca tactctgtga atattcaaaa gtaatagaat ctggcatata 1080 gttttattgattccttagcc atgggattat tgaggctttc acatatcagt gattttaaaa 1140 taccagtgttttttgctact catttgtatg tattcagtcc taggattttg aatggttttc 1200 taatatactgacatctgcat ttaatttcca gaaattaaat taattttcat gtctgaatgc 1260 tgtaattccatttatatact ttaagtaaac aaataagatt actacaatta aacacatagt 1320 tccagtttctatggccttca cttcccacct tctattagaa attaatttta tctggtattt 1380 ttaaacatttaaaaatttat catcagatat cagcatatgc ctaattatgc ctaatgaaac 1440 ttaataagcatttaattttc catcatacat tatagtcaag gcctatatac tatatataat 1500 tttggatttgtttaatctta caggctgttt tccattgtat catcaagtgg aagttcaaga 1560 cggcatcaaacaaaacaagg atgtttacag acatatgcaa agggtcagga tatctatcct 1620 ccagtatatgttaatgctta ataacaagta atcctaacag cattaaaggc caaatctgtc 1680 ctctttcccctgacttcctt acagcatgtt tatattacaa gccattcagg gacaaagaaa 1740 ccttgactaccccactgtct actaggaaca aacaaacagc aagcaaaatt cactttgaaa 1800 gcaccagtggttccattaca ttgacaacta ctaccaagat tcagtagaaa ataagtgctc 1860 aacaactaatccagattaca atatgattta gtgcatcata aaattccaac aattcagatt 1920 atttttaatcacctcagcca caactgtaaa gttgccacat tactaaagac acacacatcg 1980 tccctgttttgtagaaatat cacaaagacc aagaggctac agaaggagga aatttgcaac 2040 tgtctttgcaacaataaatc aggtatctat tctggtgtag agataggatg ttgaaagctg 2100 ccctgctatcaccagtgtag aaattaagag tagtacaata catgtacact gaaatttgcc 2160 atcgcgtgtttgtgtaaact caatgtgcac attttgtatt tcaaaaagaa aaaataaaag 2220 caaaataaaatgtttataac tctaaaaaaa aaaaaaaaaa aaa 2263 70 229 PRT Simian sp. 70 MetAsn Leu Glu Gly Leu Glu Met Ile Ala Val Leu Ile Val Ile Val 1 5 10 15Leu Phe Val Lys Leu Leu Glu Gln Phe Gly Leu Ile Glu Ala Gly Leu 20 25 30Glu Asp Ser Val Glu Asp Glu Leu Glu Met Ala Thr Val Arg His Arg 35 40 45Pro Glu Ala Leu Glu Leu Leu Glu Ala Gln Ser Lys Phe Thr Lys Lys 50 55 60Glu Leu Gln Ile Leu Tyr Arg Gly Phe Lys Asn Glu Cys Pro Ser Gly 65 70 7580 Val Val Asn Glu Glu Thr Phe Lys Glu Ile Tyr Ser Gln Phe Phe Pro 85 9095 Gln Gly Asp Ser Thr Thr Tyr Ala His Phe Leu Phe Asn Ala Phe Asp 100105 110 Thr Asp His Asn Gly Ala Val Ser Phe Glu Asp Phe Ile Lys Gly Leu115 120 125 Ser Ile Leu Leu Arg Gly Thr Val Gln Glu Lys Leu Asn Trp AlaPhe 130 135 140 Asn Leu Tyr Asp Ile Asn Lys Asp Gly Tyr Ile Thr Lys GluGlu Met 145 150 155 160 Leu Asp Ile Met Lys Ala Ile Tyr Asp Met Met GlyLys Cys Thr Tyr 165 170 175 Pro Val Leu Lys Glu Asp Ala Pro Arg Gln HisVal Glu Thr Phe Phe 180 185 190 Gln Lys Met Asp Lys Asn Lys Asp Gly ValVal Thr Ile Asp Glu Phe 195 200 205 Ile Glu Ser Cys Gln Lys Asp Glu AsnIle Met Arg Ser Met Gln Leu 210 215 220 Phe Glu Asn Val Ile 225 71 2259DNA Simian sp. 71 gtcgacagac gcccctggcc ggtggactcc tgagtcttac tcctgcaccctgcgtcccca 60 gacatgaatg tgaggagagt ggaaagcatt tcggctcagc tggaggaggccagctccaca 120 ggcggtttcc tgtatgctca gaacagcacc aagcgcagca ttaaagagcggctcatgaag 180 ctcttgccct gctcagctgc caaaacatcg tctcctgcta ttcaaaacagcgtggaagat 240 gaactggaga tggccactgt caggcatcgg cctgaggccc ttgagcttctggaagcccag 300 agcaaattta ccaagaaaga gcttcagatc ctttacagag gatttaagaacgaatgcccc 360 agtggtgttg ttaatgaaga aaccttcaaa gagatttact cgcagttctttccacaggga 420 gactctacaa catatgcaca ttttctgttc aatgcgtttg atacggaccacaatggagct 480 gtgagtttcg aggatttcat caaaggtctt tccattttgc tccgggggacagtacaagaa 540 aaactcaatt gggcatttaa tctgtatgat ataaataaag atggctacatcactaaagag 600 gaaatgcttg atataatgaa agcaatatac gacatgatgg gtaaatgtacatatcctgtc 660 ctcaaagaag atgcacccag acaacacgtc gaaacatttt ttcagaaaatggacaaaaat 720 aaagatgggg ttgttaccat agatgagttc attgaaagct gccaaaaagatgaaaacata 780 atgcgctcca tgcagctctt tgaaaatgtg atttaacttg tcaactagatcctgaatcca 840 acagacaaat gtgaactatt ctaccaccct taaagtcgga gctaccacttttagcataga 900 ttgctcagct tgacactgaa gcatattatg caaacaagct ttgttttaatataaagcaat 960 ccccaaaaga tttgagtttc tcagttataa atttgcatcc tttccataatgccactgagt 1020 tcatgggatg ttctgactca tttcatactc tgtgaatatt caaaagtaatagaatctggc 1080 atatagtttt attgattcct tagccatggg attattgagg ctttcacatatcagtgattt 1140 taaaatacca gtgttttttg ctactcattt gtatgtattc agtcctaggattttgaatgg 1200 ttttctaata tactgacatc tgcatttaat ttccagaaat taaattaattttcatgtctg 1260 aatgctgtaa ttccatttat atactttaag taaacaaata agattactacaattaaacac 1320 atagttccag tttctatggc cttcacttcc caccttctat tagaaattaattttatctgg 1380 tatttttaaa catttaaaaa tttatcatca gatatcagca tatgcctaattatgcctaat 1440 gaaacttaat aagcatttaa ttttccatca tacattatag tcaaggcctatatactatat 1500 ataattttgg atttgtttaa tcttacaggc tgttttccat tgtatcatcaagtggaagtt 1560 caagacggca tcaaacaaaa caaggatgtt tacagacata tgcaaagggtcaggatatct 1620 atcctccagt atatgttaat gcttaataac aagtaatcct aacagcattaaaggccaaat 1680 ctgtcctctt tcccctgact tccttacagc atgtttatat tacaagccattcagggacaa 1740 agaaaccttg actaccccac tgtctactag gaacaaacaa acagcaagcaaaattcactt 1800 tgaaagcacc agtggttcca ttacattgac aactactacc aagattcagtagaaaataag 1860 tgctcaacaa ctaatccaga ttacaatatg atttagtgca tcataaaattccaacaattc 1920 agattatttt taatcacctc agccacaact gtaaagttgc cacattactaaagacacaca 1980 catcgtccct gttttgtaga aatatcacaa agaccaagag gctacagaaggaggaaattt 2040 gcaactgtct ttgcaacaat aaatcaggta tctattctgg tgtagagataggatgttgaa 2100 agctgccctg ctatcaccag tgtagaaatt aagagtagta caatacatgtacactgaaat 2160 ttgccatcgc gtgtttgtgt aaactcaatg tgcacatttt gtatttcaaaaagaaaaaat 2220 aaaagcaaaa taaaatgtta aaaaaaaaaa aaaaaaaaa 2259 72 250PRT Simian sp. 72 Met Asn Val Arg Arg Val Glu Ser Ile Ser Ala Gln LeuGlu Glu Ala 1 5 10 15 Ser Ser Thr Gly Gly Phe Leu Tyr Ala Gln Asn SerThr Lys Arg Ser 20 25 30 Ile Lys Glu Arg Leu Met Lys Leu Leu Pro Cys SerAla Ala Lys Thr 35 40 45 Ser Ser Pro Ala Ile Gln Asn Ser Val Glu Asp GluLeu Glu Met Ala 50 55 60 Thr Val Arg His Arg Pro Glu Ala Leu Glu Leu LeuGlu Ala Gln Ser 65 70 75 80 Lys Phe Thr Lys Lys Glu Leu Gln Ile Leu TyrArg Gly Phe Lys Asn 85 90 95 Glu Cys Pro Ser Gly Val Val Asn Glu Glu ThrPhe Lys Glu Ile Tyr 100 105 110 Ser Gln Phe Phe Pro Gln Gly Asp Ser ThrThr Tyr Ala His Phe Leu 115 120 125 Phe Asn Ala Phe Asp Thr Asp His AsnGly Ala Val Ser Phe Glu Asp 130 135 140 Phe Ile Lys Gly Leu Ser Ile LeuLeu Arg Gly Thr Val Gln Glu Lys 145 150 155 160 Leu Asn Trp Ala Phe AsnLeu Tyr Asp Ile Asn Lys Asp Gly Tyr Ile 165 170 175 Thr Lys Glu Glu MetLeu Asp Ile Met Lys Ala Ile Tyr Asp Met Met 180 185 190 Gly Lys Cys ThrTyr Pro Val Leu Lys Glu Asp Ala Pro Arg Gln His 195 200 205 Val Glu ThrPhe Phe Gln Lys Met Asp Lys Asn Lys Asp Gly Val Val 210 215 220 Thr IleAsp Glu Phe Ile Glu Ser Cys Gln Lys Asp Glu Asn Ile Met 225 230 235 240Arg Ser Met Gln Leu Phe Glu Asn Val Ile 245 250

What is claimed is:
 1. A method for identifying a compound suitable for treating a cardiovascular disorder comprising: a) contacting a PCIP polypeptide or a fragment thereof, or a cell expressing a PCIP polypeptide or a fragment thereof, with a test compound; and b) determining whether said PCIP polypeptide or fragment thereof, binds to said test compound, thereby identifying a compound suitable for treating a cardiovascular disorder.
 2. The method of claim 1, wherein the binding of said test compound to said PCIP polypeptide or fragment thereof, is detected by a method selected from the group consisting of: a) detection of binding by direct detection of test compound/polypeptide binding; b) detection of binding using a competition binding assay; and c) detection of binding using an assay for PCIP activity.
 3. A method for identifying a compound suitable for treating a cardiovascular disorder, comprising: a) incubating a cell expressing i) a potassium channel comprising a Kv4.3 or Kv4.2 subunit, or a fragment of a potassium channel comprising a Kv4.3 or Kv4.2 subunit, and ii) a PCIP polypeptide or a fragment thereof, in the presence and absence of a candidate compound; and b) determining whether the presence of the candidate compound modulates the interaction of the potassium channel or fragment thereof with said PCIP polypeptide or fragment thereof, thereby identifying a compound suitable for treating a cardiovascular disorder.
 4. A method for treating a cardiovascular disorder comprising contacting a potassium channel with an effective amount of a compound that modulates the binding of a PCIP protein to said potassium channel.
 5. A method for determining if a subject is at risk for a cardiovascular disorder comprising detecting, in a sample of cells from the subject an alteration in a PCIP gene which causes a mutated PCIP polypeptide to be produced.
 6. A method for determining if a subject is at risk for a cardiovascular disorder comprising detecting, in a sample of cells from the subject an alteration in a PCIP gene which causes abnormal expression of a PCIP polypeptide.
 7. A method for determining if a subject is at risk for a cardiovascular disorder comprising detecting, in a sample of cells from the subject an alteration in a PCIP gene which causes abnormal processing of a PCIP polypeptide.
 8. A method for identifying a subject suffering from a cardiovascular disorder comprising detecting, in a sample of cells from the subject an alteration in a PCIP gene which causes a mutated PCIP polypeptide to be produced.
 9. A method for identifying a subject suffering from a cardiovascular disorder comprising detecting, in a sample of cells from the subject an alteration in a PCIP gene which causes abnormal expression of a PCIP polypeptide.
 10. A method for identifying a subject suffering from a cardiovascular disorder comprising detecting, in a sample of cells from the subject an alteration in a PCIP gene which causes abnormal processing of a PCIP polypeptide.
 11. The method of any one of claims 1, 3, 4, 5, 6, 7, 8, 9, or 10, wherein said cardiovascular disorder is associated with an abnormal I_(to) current.
 12. The method of any one of claims 1, 3, 4, 5, 6, 7, 8, 9, or 10, wherein said PCIP is 9q.
 13. The method of any one of claims 1, 3, 4, 5, 6, 7, 8, 9, or 10, wherein said PCIP is 8t.
 14. The method of any one of claims 1, 3, 4, 5, 6, 7, 8, 9, or 10, wherein said PCIP is p19.
 15. The method of any one of claims 1, 3, 4, 5, 6, 7, 8, 9, or 10, wherein said cardiovascular disorder is long-QT syndrome.
 16. The method of any one of claims 1, 3, 4, 5, 6, 7, 8, 9, or 10, wherein said cardiovascular disorder is congestive heart failure. 